bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–06–13
fifty papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade.
  2. NRAS mutant melanoma: Towards better therapies.
  3. Establishment of cultured primary acral melanoma cells and animal models for Chinese patients.
  4. Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma.
  5. Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study.
  6. Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS).
  7. Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib.
  8. Association Between FSIP2 Mutation and an Improved Efficacy of Immune Checkpoint Inhibitors in Patients With Skin Cutaneous Melanoma.
  9. Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma.
  10. miR-34a inhibits melanoma growth by targeting ZEB1.
  11. Soluble immune checkpoints and T-cell subsets in blood as biomarkers for resistance to immunotherapy in melanoma patients.
  12. Risk Models for Advanced Melanoma Patients Under Anti-PD-1 Monotherapy-Ad hoc Analyses of Pooled Data From Two Clinical Trials.
  13. Expression of cathepsins B and D by cancer stem cells in head and neck metastatic malignant melanoma.
  14. Clinical characteristics and therapy response in unresectable melanoma patients stage IIIB-IIID with in-transit and satellite metastases.
  15. A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells.
  16. Dual covalent inhibition of PKM and IMPDH targets metabolism in cutaneous metastatic melanoma.
  17. Sentinel lymph node biopsy in melanoma: beyond histologic factors.
  18. Melanoma genomics: a state-of-the-art review of practical clinical applications.
  19. Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma.
  20. Impact of molecular testing in advanced melanoma on outcomes in a tertiary cancer center and as reported in a publicly available database.
  21. Suppressive role of microRNA-130b-3p in ferroptosis in melanoma cells correlates with DKK1 inhibition and Nrf2-HO-1 pathway activation.
  22. Effect of melanoma stem cells on melanoma metastasis.
  23. Therapy of uveal melanoma A Review.
  24. Up-regulation of KISS1 as a novel target of Let-7i in melanoma serves as a potential suppressor of migration and proliferation in vitro.
  25. Is Melanoma Overdiagnosed? A Review of the Evidence.
  26. Functional in vivo characterization of sox10 enhancers in neural crest and melanoma development.
  27. Identification and Validation of Immune-Related lncRNA Signature as a Prognostic Model for Skin Cutaneous Melanoma.
  28. The role of immunotherapy and molecular‑targeted therapy in the treatment of melanoma (Review).
  29. Development and in vivo evaluation of fused benzazole analogs of anti-melanoma agent HA15.
  30. FUT8-AS1 Inhibits the Malignancy of Melanoma Through Promoting miR-145-5p Biogenesis and Suppressing NRAS/MAPK Signaling.
  31. UDP-GlcNAc-1-phosphotransferase is a clinically important regulator of human and mouse hair pigmentation.
  32. Association between income and suspected non-melanoma and melanoma skin cancers among participants of the American Academy of Dermatology's SPOT Skin Cancer® screening program - A cross-sectional analysis.
  33. Evaluation of 2-methoxyestradiol serum levels as a potential prognostic marker in malignant melanoma.
  34. Acetone Extract of Cornus officinalis Leaves Exerts Anti-Melanoma Effects via Inhibiting STAT3 Signaling.
  35. Viral Molecular Mimicry Influences the Antitumor Immune Response in Murine and Human Melanoma.
  36. Posterior Reversible Encephalopathy Syndrome (PRES) and Drug-Induced Hypersensitivity Syndrome (DIHS) following Immunotherapy and BRAF/MEK Inhibition with Continued Response in Metastatic Melanoma.
  37. Spatiotemporal Analysis of B Cell- and Antibody Secreting Cell-Subsets in Human Melanoma Reveals Metastasis-, Tumor Stage-, and Age-Associated Dynamics.
  38. Treatment Delay in Melanoma: A Risk Factor Analysis of an Impending Crisis.
  39. Acute exudative polymorphous vitelliform maculopathy during pembrolizumab treatment for metastatic melanoma: a case report.
  40. Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors.
  41. Incidence, predictors, and survival impact of acute kidney injury in patients with melanoma treated with immune checkpoint inhibitors: a 10-year single-institution analysis.
  42. Updates and new medical treatments for vitiligo (Review).
  43. Dermal papilla cells and melanocytes response to physiological oxygen levels depends on their interactions.
  44. Physio-pathological effects of m6A modification and its potential contribution to melanoma.
  45. Propionic acid produced by Cutibacterium acnes fermentation ameliorates ultraviolet B-induced melanin synthesis.
  46. ASO Visual Abstract: Assessment of Frailty Can Guide Decision Making for Utilization of Sentinel Lymph Node Biopsy in Patients with Thick Melanoma.
  47. Socioeconomic factors, stress, hair cortisol, and white matter microstructure in children.
  48. RIP1-mediated necroptosis facilitates oxidative stress-induced melanocyte death offering insight into vitiligo.
  49. Recent Advances in the Treatment of Melanoma.
  50. Barriers to Physician-Based Skin Examinations for Adolescent and Young Adult Survivors of Melanoma in the Project Forward Study.
  1. Mol Cancer. 2021 Jun 06. 20(1): 85
    Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade.
    Chi Yan, Nabil Saleh, Jinming Yang, Caroline A Nebhan, Anna E Vilgelm, E Premkumar Reddy, Joseph T Roland, Douglas B Johnson, Sheau-Chiann Chen, Rebecca L Shattuck-Brandt, Gregory D Ayers, Ann Richmond.
       BACKGROUND: While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.
    METHODS: Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAFwt and BRAFmut melanoma and analyzed in reference to patient data.
    RESULTS: RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB.
    CONCLUSIONS: Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.
    TRIAL REGISTRATION: NCT01205815 (Sept 17, 2010).
    Keywords:  CD40; Immune checkpoint blockade; Immunogenic cell death; Melanoma; RAS/RAF/PI3K
    DOI:  https://doi.org/10.1186/s12943-021-01366-y
  2. Cancer Treat Rev. 2021 May 29. pii: S0305-7372(21)00086-4. [Epub ahead of print]99 102238
    NRAS mutant melanoma: Towards better therapies.
    Tijana Randic, Ines Kozar, Christiane Margue, Jochen Utikal, Stephanie Kreis.
      Genetic alterations affecting RAS proteins are commonly found in human cancers. Roughly a fourth of melanoma patients carry activating NRAS mutations, rendering this malignancy particularly challenging to treat. Although the development of targeted as well as immunotherapies led to a substantial improvement in the overall survival of non-NRASmut melanoma patients (e.g. BRAFmut), patients with NRASmut melanomas have an overall poorer prognosis due to the high aggressiveness of RASmut tumors, lack of efficient targeted therapies or rapidly emerging resistance to existing treatments. Understanding how NRAS-driven melanomas develop therapy resistance by maintaining cell cycle progression and survival is crucial to develop more effective and specific treatments for this group of melanoma patients. In this review, we provide an updated summary of currently available therapeutic options for NRASmut melanoma patients with a focus on combined inhibition of MAPK signaling and CDK4/6-driven cell cycle progression and mechanisms of the inevitably developing resistance to these treatments. We conclude with an outlook on the most promising novel therapeutic approaches for melanoma patients with constitutively active NRAS. STATEMENT OF SIGNIFICANCE: An estimated 75000 patients are affected by NRASmut melanoma each year and these patients still have a shorter progression-free survival than BRAFmut melanomas. Both intrinsic and acquired resistance occur in NRAS-driven melanomas once treated with single or combined targeted therapies involving MAPK and CDK4/6 inhibitors and/or checkpoint inhibiting immunotherapy. Oncolytic viruses, mRNA-based vaccinations, as well as targeted triple-agent therapy are promising alternatives, which could soon contribute to improved progression-free survival of the NRASmut melanoma patient group.
    Keywords:  Cutaneous melanoma; MEKi/CDK4/6i dual therapy; NRAS mutation; New combination therapies; Resistance mechanisms
    DOI:  https://doi.org/10.1016/j.ctrv.2021.102238
  3. Pigment Cell Melanoma Res. 2021 Jun 07.
    Establishment of cultured primary acral melanoma cells and animal models for Chinese patients.
    Rui Hu, Shuang Zhao, Juan Su, Xiang Chen, Mingzhu Yin.
      Acral melanoma is the major subtype of melanoma in Chinese patients. However, a majority of current studies focused on non-acral melanoma. Most immortalized melanoma cell lines and primary cells were not from acral melanoma. Besides, there are rarely reports about methods for establishing primary acral melanoma cell cultures and related animal models. Here, we present four new human primary acral melanoma cell lines. To determine the mutational profile of the established primary melanoma cells for future targeted use, we performed exome sequencing. We next examined cell proliferation of the primary acral melanoma cells by colony-formation assays and CCK8 assay. We also evaluated the proliferative and metastatic potential of XYAM-4 in vivo. We report a detailed protocol for establishing cultured primary acral melanoma cells for Chinese patients and related animal models. We also summarize the features in our acral melanoma cell lines and the exist acral melanoma cell lines. This will provide an effective research tool for research on drug responses and individualized treatment for Chinese patients and comparative studies of melanomas between western and Chinese populations.
    Keywords:  Acral melanoma; Chinese patients; Melanoma mutation; Primary cell; Primary cell culture
    DOI:  https://doi.org/10.1111/pcmr.12996
  4. J Immunother Cancer. 2021 Jun;pii: e002273. [Epub ahead of print]9(6):
    Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma.
    Kevin T Lynch, Samuel J Young, Max O Meneveau, Nolan A Wages, Victor H Engelhard, Craig L Slingluff, Ileana S Mauldin.
       BACKGROUND: Tertiary lymphoid structures (TLSs) are immune aggregates in peripheral tissues that may support adaptive immune responses. Their presence has been associated with clinical response to checkpoint blockade therapy (CBT), but it is unknown whether TLS have prognostic significance independent of CBT in melanoma. We hypothesized that TLS in melanoma metastases would be associated with increased intratumoral lymphocyte infiltration, but that the intra-TLS immunological milieu would be distinct from the intratumoral immunological milieu. We also hypothesized that the presence of TLS would be associated with improved survival, and that TLS maturation or intra-TLS lymphocyte activity would also correlate with survival.
    METHODS: Cutaneous melanoma metastases (CMM) from 64 patients were evaluated by multiplex immunofluorescence for the presence and maturation status of TLS. Intra-TLS lymphocyte density, proliferation and B-cell Ig somatic hypermutation (AID+) were analyzed, as were markers of T-cell exhaustion and Th1/Tc1 differentiation. Associations between TLS maturation and intra-TLS immunologic activity were assessed, as well as associations with intratumoral immune cell infiltration. Independent associations with overall survival (OS) were assessed using log-rank tests and Cox proportional hazards models.
    RESULTS: TLS were identified in 30 (47%) of 64 CMM (TLS+) and were associated with increased intratumoral lymphocyte infiltration. However, proliferation of intra-TLS lymphocytes did not correlate with intratumoral lymphocyte proliferation. Most were early TLS; however, subsets of primary or secondary follicle-like TLS were also present. TLS+ lesions were associated with lower risk of tumor recurrence after metastasectomy and with improved OS in multivariate analyses (HR 0.51, p=0.04). OS was longer for TLS with low fractions of CD21+ B-cells (HR 0.29, p=0.02) and shorter for those with low AID+ fraction of B-cells (HR 2.74, p=0.03).
    CONCLUSIONS: The presence of TLS in CMMs is associated with improved OS in patients treated with surgery before CBT, but TLS vary widely in maturation state, in proportions of proliferating T and B cells, and in markers of B cell function, including AID and CD21. Importantly, these features have additional prognostic significance, which suggest that some TLS may have regulatory function, while others functioning to support antigen-driven immune responses, depending on the cellular composition and activation status.
    Keywords:  B-lymphocytes; cellular; immunity; melanoma; tumor microenvironment
    DOI:  https://doi.org/10.1136/jitc-2020-002273
  5. Front Oncol. 2021 ;11 672172
    Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study.
    Katharina C Kähler, Ralf Gutzmer, Friedegrund Meier, Lisa Zimmer, Markus Heppt, Anja Gesierich, Kai-Martin Thoms, Jochen Utikal, Jessica C Hassel, Carmen Loquai, Claudia Pföhler, Lucie Heinzerling, Martin Kaatz, Daniela Göppner, Annette Pflugfelder, Ann-Sophie Bohne, Imke Satzger, Lydia Reinhardt, Jan-Malte Placke, Dirk Schadendorf, Selma Ugurel.
       Background: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome.
    Methods: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS).
    Results: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema.
    Conclusions: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment.
    Keywords:  BRAF/MEK inhibition; cobimetinib; melanoma; skin toxicity; therapy outcome; vemurafenib
    DOI:  https://doi.org/10.3389/fonc.2021.672172
  6. Eur J Cancer. 2021 Jun 03. pii: S0959-8049(21)00274-4. [Epub ahead of print]152 116-128
    Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS).
    Helen Gogas, Reinhard Dummer, Paolo A Ascierto, Ana Arance, Mario Mandalà, Gabriella Liszkay, Claus Garbe, Dirk Schadendorf, Ivana Krajsová, Ralf Gutzmer, Vanna Chiarion Sileni, Caroline Dutriaux, Naoya Yamazaki, Carmen Loquai, Paola Queirolo, Groot Jan de Willem, Abir Tadmouri Sellier, Jeanne Suissa, Juliette Murris, Ashwin Gollerkeri, Caroline Robert, Keith T Flaherty.
       BACKGROUND: In COLUMBUS, treatment with encorafenib plus binimetinib in patients with advanced BRAF-mutant melanoma showed improved progression-free and overall survival with favourable tolerability compared to vemurafenib treatment. Here, results on health-related quality of life (HRQoL) are presented.
    METHODS: COLUMBUS was a two-part, open-label, randomised, phase III study in patients with BRAF-mutant melanoma. In PART-I, 577 patients were randomised (1:1:1) to encorafenib plus binimetinib, encorafenib or vemurafenib. The primary objective was to assess progression-free survival. As a secondary objective, HRQoL was assessed by the EQ-5D, the EORTC QLQ-C30 and the FACT-M questionnaires. Furthermore, time to definitive 10% deterioration was estimated with a Kaplan-Meier analysis and differences in mean scores between groups were calculated with a mixed-effect model for repeated measures. Hospitalisation rate and the impact of hospitalisation on HRQoL were also assessed.
    RESULTS: Patients receiving the combination treatment showed improvement of their FACT-M and EORTC QLQ-C30 global health status scores, compared to those receiving vemurafenib (post-baseline score differences: 3.03 [p < 0.0001] for FACT M and 5.28 [p = 0.0042] for EORTC QLQ-C30), indicative of a meaningful change in patient's status. Furthermore, a delay in the deterioration of QoL was observed in non-hospitalised patients compared to hospitalised patients (hazard ratio [95% CI]: 1.16 [0.80; 1.68] for EORTC QLQ-C30 and 1.27 [0.81; 1.99] for FACT-M) and a risk reduction of 10% deterioration, favoured the combination in both groups.
    CONCLUSION: The improved efficacy of encorafenib plus binimetinib compared to vemurafenib, translates into a positive impact on the perceived health status as assessed by the HRQoL questionnaires. The study is registered with ClinicalTrials.gov, number NCT01909453 and EudraCT number 2013-001176-38.
    Keywords:  BRAF(V600E−K) mutant Melanoma; BRAF/MEK inhibitors Combination; Encorafenib plus binimetinib; Health-related quality of life; Hospitalisation rate
    DOI:  https://doi.org/10.1016/j.ejca.2021.04.028
  7. Clin Cancer Res. 2021 Jun 09. pii: clincanres.3586.2020. [Epub ahead of print]
    Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib.
    Jan C Brase, Robert F H Walter, Alexander Savchenko, Daniel Gusenleitner, James Garrett, Tobias Torsten Schimming, Renáta Váraljai, Deborah Castelletti, Ju-Young Kim, Naveen K Dakappagari, Ken Schultz, Caroline Robert, Georgina V Long, Paul D Nathan, Antoni Ribas, Keith T Flaherty, Boguslawa Karaszewska, Jacob Schachter, Antje Sucker, Kurt W Schmid, Lisa Zimmer, Elisabeth Livingstone, Eduard Gasal, Dirk Schadendorf, Alexander Roesch.
       PURPOSE: Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.
    EXPERIMENTAL DESIGN: We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600-mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening.
    RESULTS: Baseline cell cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months-not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months [95% CI, 13.4-38.6 months]). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased mitogen-activated protein kinase activity and increased expression of immunosuppressive markers.
    CONCLUSIONS: B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-3586
  8. Front Mol Biosci. 2021 ;8 629330
    Association Between FSIP2 Mutation and an Improved Efficacy of Immune Checkpoint Inhibitors in Patients With Skin Cutaneous Melanoma.
    Haoxuan Ying, Anqi Lin, Junyi Liang, Jian Zhang, Peng Luo.
       Background: Immune checkpoint inhibitors (ICIs) have shown remarkable success in treating skin cutaneous melanoma (SKCM); however, the response to treatment varies greatly between patients. Considering that the efficacy of ICI treatment is influenced by many factors, we selected the Fibrosheath interacting protein 2 (FSIP2) gene and systematically analyzed its potential to predict the efficacy of ICI treatment.
    Methods: Patient data were collected from an ICI treatment cohort (n = 120) and a The Cancer Genome Atlas (TCGA)-SKCM cohort (n = 467). The data were divided into an FSIP2-mutant (MT) group and FSIP2-wild-type (WT) group according to FSIP2 mutation status. In this study, we analyzed the patients' overall survival rate, tumor mutational burden (TMB), neoantigen load (NAL), copy number variation (CNV), cell infiltration data and immune-related genes. We used gene set enrichment analysis (GSEA) to delineate biological pathways and processes associated with the efficacy of immunotherapy.
    Results: The efficacy of ICI treatment of SKCM patients with FSIP2 mutation was significantly better than that of patients without FSIP2 mutation. The patients in the FSIP2-MT group had higher tumor immunogenicity and lower regulatory T cell (Treg) infiltration. Results of GSEA showed that pathways related to tumor progression (MAPK and FGFR), immunomodulation, and IL-2 synthesis inhibition were significantly downregulated in the FSIP2-MT group.
    Conclusion: Our research suggests that the FSIP2 gene has the potential to predict the efficacy of ICI treatment. The high tumor immunogenicity and low Treg levels observed may be closely related to the fact that patients with FSIP2-MT can benefit from ICI treatment.
    Keywords:  Fibrosheath interacting protein 2; immune checkpoint inhibitor; regulatory T cell; skin cutaneous melanoma; tumor mutation burden
    DOI:  https://doi.org/10.3389/fmolb.2021.629330
  9. Nat Immunol. 2021 Jun 07.
    Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma.
    Nicolas Jacquelot, Cyril Seillet, Minyu Wang, Angela Pizzolla, Yang Liao, Soroor Hediyeh-Zadeh, Sharon Grisaru-Tal, Cynthia Louis, Qiutong Huang, Jaring Schreuder, Fernando Souza-Fonseca-Guimaraes, Carolyn A de Graaf, Kevin Thia, Sean Macdonald, Mary Camilleri, Kylie Luong, Shengbo Zhang, Michael Chopin, Tristan Molden-Hauer, Stephen L Nutt, Viktor Umansky, Bogoljub Ciric, Joanna R Groom, Paul S Foster, Philip M Hansbro, Andrew N J McKenzie, Daniel H D Gray, Andreas Behren, Jonathan Cebon, Eric Vivier, Ian P Wicks, Joseph A Trapani, Ariel Munitz, Melissa J Davis, Wei Shi, Paul J Neeson, Gabrielle T Belz.
      Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
    DOI:  https://doi.org/10.1038/s41590-021-00943-z
  10. Aging (Albany NY). 2021 Jun 08. 13(undefined):
    miR-34a inhibits melanoma growth by targeting ZEB1.
    Yazhen Xu, Bingyu Guo, Xiaoyan Liu, Kai Tao.
      Melanoma is a highly lethal cutaneous cancer with the tendency for early invasion and metastasis. Integrated miRNA transcriptome sequence analysis of human melanoma tumors and adjacent control tissues identified 17 miRNAs differentially expressed in melanoma tissues: let-7a-5p, let-7b-5p, let-7c, miR-374a-3p, miR-100-5p, miR-7, miR-195, miR-1908, miR-214, miR-221, miR-199a-5p, miR-21, miR-18, miR-34a, miR-199a-3p, miR-92a and miR-106b. Among these, miR-34a was most significantly down-regulated in melanoma tissues, and its expression correlated with TNM melanoma stage. miR-34a overexpression inhibited expression and activity of the transcription factor ZEB1, resulting in decreased proliferation and migration of melanoma cells. Moreover, miR-34a overexpression inhibited ZEB1 expression and melanoma tumor growth in vivo, in a melanoma nude mouse model. Together, these findings demonstrate that miR-34a inhibits melanoma growth by targeting the proto-oncogene ZEB1 and suggest the miR-34a -ZEB1 axis may serve as a novel target for melanoma treatment.
    Keywords:  ZEB1; melanoma; miR-34a; migration; proliferation
    DOI:  https://doi.org/10.18632/aging.203114
  11. Oncoimmunology. 2021 May 25. 10(1): 1926762
    Soluble immune checkpoints and T-cell subsets in blood as biomarkers for resistance to immunotherapy in melanoma patients.
    Devayani Machiraju, Melanie Wiecken, Nina Lang, Ingrid Hülsmeyer, Jasmin Roth, Timo E Schank, Rosa Eurich, Niels Halama, Alexander Enk, Jessica C Hassel.
      Different mechanisms lead to immune checkpoint inhibitor (ICI) resistance. Identifying clinically useful biomarkers might improve drug selection and patients' therapy. We analyzed the soluble immune checkpoints sPD1, sPDL1, sLAG3, and sTIM3 using ELISA and their expression on circulating T cells using FACS in pre- and on-treatment blood samples of ICI treated melanoma patients. In addition, pre-treatment melanoma metastases were stained for TIM3 and LAG3 expression by IHC. Results were correlated with treatment response and progression-free survival (PFS). Resistance to anti-PD1 treatment (n = 48) was associated with high pre-treatment serum levels of sLAG3 (DCR: p = .009; PFS: p = .018; ROC cutoff >148 pg/ml) but not sPD1, sPDL1 or sTIM3. In contrast, resistance to ipilimumab plus nivolumab (n = 42) was associated with high levels of sPD1 (DCR: p = .019, PFS: p = .046; ROC cutoff >167 pg/ml) but not sPDL1, sLAG3 or sTIM3. Both treatment regimens shared a profound increase of sPD1 serum levels with treatment (p < .0001). FACS analysis revealed reduced frequencies of CD3+ CD8+ PD1 + T cells (p = .028) in anti-PD1-resistant patients, whereas increased frequencies of CD3+ CD4+ LAG3 + T cells characterized patients resistant to ipilimumab plus nivolumab (p = .033). Unlike anti-PD1 monotherapy, combination blockade significantly increased proliferating T cells (CD3+ CD8+ Ki67 + T cells; p < .0001) and eosinophils (p = .001). In melanoma metastases, an increased infiltration with TIM3+ or LAG3 + T cells in the tumor microenvironment correlated with a shorter PFS under anti-PD1 treatment (TIM3: p = .019, LAG3: p = .07). Different soluble immune checkpoints characterized checkpoint inhibitor-resistant melanoma. Measuring these serum markers may have the potential to be used in clinical routine.
    Keywords:  Melanoma; immune checkpoints; immunotherapy; t lymphocytes
    DOI:  https://doi.org/10.1080/2162402X.2021.1926762
  12. Front Oncol. 2021 ;11 639085
    Risk Models for Advanced Melanoma Patients Under Anti-PD-1 Monotherapy-Ad hoc Analyses of Pooled Data From Two Clinical Trials.
    Xue Bai, Jie Dai, Caili Li, Chuanliang Cui, Lili Mao, Xiaoting Wei, Xinan Sheng, Zhihong Chi, Xieqiao Yan, Bixia Tang, Bin Lian, Xuan Wang, Li Zhou, Siming Li, Yan Kong, Zhonghui Qi, Huayan Xu, Rong Duan, Jun Guo, Lu Si.
      Background: The best response and survival outcomes between advanced melanoma patients treated with the anti-PD-1 monotherapy vary greatly, rendering a risk model in need to optimally stratify patients based on their likelihood to benefit from the said treatment. Methods: We performed an ad hoc analysis of 89 advanced melanoma patients treated with the anti-PD-1 monotherapy from two prospective clinical trials at the Peking University Cancer Hospital from April 2016 to May 2018. Clinicodemographical characteristics, baseline and early-on-treatment (median 0.6 months after anti-PD-1 monotherapy initiation) routine laboratory variables, including complete blood count and general chemistry, and best response/survival data were extracted and analyzed in both univariate and multivariate logistic and Cox proportional hazard models. Results: After three rounds of screening, risk factors associated with a poorer PFS included a high pre-treatment neutrophil, derived neutrophil-lymphocyte ratio (dNLR), low pre-treatment hemoglobin, and low early-on-/pre-treatment fold change of eosinophil; those with a poorer OS included a high pre-treatment neutrophil, eosinophil, PLT, early-on/pre-treatment fold change of LDH and neutrophil; and those with a poorer best response included a high pre-treatment NLR and early-on-/pre-treatment LDH fold change. Risk models (scale: low, median-low, median high, and high risk) were established based on these risk factors as dichotomous variables and M stage (with vs. without distant metastasis) for PFS (HR 1.976, 95% CI, 1.507-2.592, P < 0.001), OS (HR 2.348, 95% CI, 1.688-3.266), and non-responder (OR 3.586, 95% CI, 1.668-7.713, P = 0.001), respectively. For patients with low, median-low, median-high, and high risks of developing disease progression (PD), six-month PFS rates were 64.3% (95% CI, 43.5-95.0%), 37.5% (95% CI, 22.4-62.9%), 9.1% (95% CI, 3.1-26.7%), and 0%, respectively. For patients with OS risks of low, median-low, median-high, and high, OS rates at 12 months were 82.5% (95% CI, 63.1-100%), 76.6% (95% CI, 58.4-100%), 42.1% (95% CI, 26.3-67.3%), and 23.9% (95% CI, 11.1-51.3%), respectively. For patients with risks of low, median-low, median-high, and high of being a non-responder, objective response rates were 50.0% (95% CI, 15.7-84.3%), 27.8% (95% CI, 9.7-53.5%), 10.3% (95% CI, 2.9-24.2%), and 0%, respectively. Conclusion: A risk scoring model based on the clinicodemographical characteristics and easily obtainable routinely tested laboratory biomarkers may facilitate the best response and survival outcome prediction and personalized therapeutic decision making for the anti-PD-1 monotherapy treated advanced melanoma patients in Asia.
    Keywords:  PD-1; best response; melanoma; overall survival; progression free survival; risk model
    DOI:  https://doi.org/10.3389/fonc.2021.639085
  13. Melanoma Res. 2021 Jun 10.
    Expression of cathepsins B and D by cancer stem cells in head and neck metastatic malignant melanoma.
    Adam B Sangster, Bridget Chang-McDonald, Josie Patel, Nicholas Bockett, Erin Paterson, Paul F Davis, Swee T Tan.
      We have previously demonstrated cancer stem cell (CSC) subpopulations in head and neck metastatic malignant melanoma (HNmMM), and the expression of components of the renin-angiotensin system (RAS) by these CSCs. Cathepsins B, D and G are involved in carcinogenesis and constitute bypass loops of the RAS. This study investigated the expression and localization of cathepsins B, D and G, in relation to these CSCs. Immunohistochemical staining demonstrated expression of cathepsins B, D and G in HNmMM sections from all 20 patients. Western blotting confirmed the presence of cathepsins B and D proteins in all six HNmMM tissue samples and four HNmMM-derived primary cell lines. RT-qPCR showed transcript expression of cathepsins B, D and G in all six HNmMM tissue samples, and cathepsins B and D but not cathepsin G in all four HNmMM-derived primary cell lines. Enzymatic activity assays demonstrated cathepsins B and D were active in all six HNmMM tissue samples. Immunofluorescence staining performed on two of the HNmMM tissue samples demonstrated expression of cathepsins B and D by the CSCs, and cathepsin G by cells within the peritumoral. Our novel findings suggest the possibility of targeting these CSCs by modulation of paracrine RAS signaling.
    DOI:  https://doi.org/10.1097/CMR.0000000000000752
  14. Eur J Cancer. 2021 Jun 05. pii: S0959-8049(21)00278-1. [Epub ahead of print]152 139-154
    Clinical characteristics and therapy response in unresectable melanoma patients stage IIIB-IIID with in-transit and satellite metastases.
    Anne Zaremba, Manuel Philip, Jessica C Hassel, Valerie Glutsch, Zeno Fiocco, Carmen Loquai, David Rafei-Shamsabadi, Ralf Gutzmer, Jochen Utikal, Sebastian Haferkamp, Lydia Reinhardt, Katharina C Kähler, Carsten Weishaupt, Alvaro Moreira, Kai-Martin Thoms, Tabea Wilhelm, Claudia Pföhler, Alexander Roesch, Selma Ugurel, Lisa Zimmer, Nadine Stadtler, Antje Sucker, Felix Kiecker, Lucie Heinzerling, Friedegund Meier, Frank Meiss, Max Schlaak, Bastian Schilling, Susanne Horn, Dirk Schadendorf, Elisabeth Livingstone.
       INTRODUCTION: Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients.
    METHODS: In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately.
    RESULTS: Median follow-up time was 30.5 (range 0.8-154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40-0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45-1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%.
    CONCLUSION: Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.
    Keywords:  Immune checkpoint blockade; In-transit; Intralesional therapy; Melanoma; Prognosis; Satellite; Survival; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ejca.2021.04.032
  15. Cell Death Dis. 2021 Jun 08. 12(6): 591
    A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells.
    Jie Wen, Wenqian Chen, Baoxiang Zhao, Qiuping Xu, Chang Liu, Qun Zhang, Zhiwei Xie, Yonggan Yan, Jing Guo, Jun Huang, Junying Miao, Xunwei Wu.
      p53, the major tumor suppressor, is frequently mutated in many cancers, and up to 84% of human melanomas harbor wild-type p53, which is considered to be an ideal target for melanoma therapy. Here, we evaluated the antitumor activity of a carbazole derivative, 9-ethyl-9H-carbazole-3-carbaldehyde (ECCA), on melanoma cells. ECCA had a selectively strong inhibitory activity against the growth of BRAF-mutated and BRAF-wild-type melanoma cells but had little effect on normal human primary melanocytes. ECCA inhibited melanoma cell growth by increasing cell apoptosis, which was associated with the upregulation of caspase activities and was significantly abrogated by the addition of a caspase inhibitor. In vivo assays confirmed that ECCA suppressed melanoma growth by enhancing cell apoptosis and reducing cell proliferation, and importantly ECCA did not have any evident toxic effects on normal tissues. RNA-Seq analysis identified several pathways related to cell apoptosis that were affected by ECCA, notably, activation of the p53 signaling pathway. Biochemical assays demonstrated that ECCA enhanced the phosphorylation of p53 at Ser15 in melanoma cells harboring wild-type p53, and importantly, the knockdown or deletion of p53 in those cells counteracted the ECCA-induced apoptosis, as well as senescence. Further investigations revealed that ECCA enhanced the phosphorylation of p38-MAPK and c-Jun N-terminal kinase (JNK), and treatment with either a p38-MAPK or a JNK inhibitor rescued the cell growth inhibition elicited by ECCA, which depended on the expression of the p53 gene. Finally, the combination of ECCA with a BRAF inhibitor significantly enhanced the growth inhibition of melanoma cells. In summary, our study demonstrates that the carbazole derivative, ECCA, induces melanoma cell apoptosis and senescence through the activation of p53 to significantly and selectively suppress the growth of melanoma cells without affecting normal human melanocytes, suggesting its potential to develop a new drug for melanoma therapy.
    DOI:  https://doi.org/10.1038/s41419-021-03867-6
  16. Cancer Res. 2021 Jun 07. pii: canres.2114.2020. [Epub ahead of print]
    Dual covalent inhibition of PKM and IMPDH targets metabolism in cutaneous metastatic melanoma.
    Marwa Zerhouni, Anthony R Martin, Nathan Furstoss, Vincent S Gutierrez, Emilie Jaune, Nedra Tekaya, Guillaume E Beranger, Patricia Abbe, Claire Regazzetti, Hella Amdouni, Mohsine Driowya, Patrice Dubreuil, Frédéric Luciano, Arnaud Jacquel, Meri K Tulic, Thomas Cluzeau, Brendan P O'Hara, Issam Ben-Sahra, Thierry Passeron, Rachid Benhida, Guillaume Robert, Patrick Auberger, Stéphane Rocchi.
      Overcoming acquired drug resistance is a primary challenge in cancer treatment. Notably, more than 50% of BRAFV600E cutaneous metastatic melanoma (CMM) patients eventually develop resistance to BRAF inhibitors. Resistant cells undergo metabolic reprogramming which profoundly influences therapeutic response and promotes tumor progression. Uncovering metabolic vulnerabilities could help suppress CMM tumor growth and overcome drug resistance. Here we identified a drug, HA344, that concomitantly targets two distinct metabolic hubs in cancer cells. HA344 inhibited the final and rate-limiting step of glycolysis through its covalent binding to the pyruvate kinase M2 (PKM2) enzyme, and it concurrently blocked the activity of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo guanylate synthesis. As a consequence, HA344 efficiently targeted vemurafemib-sensitive and -resistant CMM cells and impaired CMM xenograft tumor growth in mice. In addition, HA344 acted synergistically with BRAF inhibitors on CMM cell lines in vitro. Thus, the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2114
  17. Clin Exp Metastasis. 2021 Jun 08.
    Sentinel lymph node biopsy in melanoma: beyond histologic factors.
    Michael J Carr, Federico A Monzon, Jonathan S Zager.
      Sentinel lymph node (SLN) biopsy should be performed with the technical expertise required to correctly identify the sentinel node, in the context of understanding both the likelihood of positivity in a given patient and the prognostic significance of a positive or negative result. National Comprehensive Cancer Network guidelines recommend SLN biopsy for all cutaneous melanoma patients with primary tumor thickness greater than 1 mm and in select patients with thickness between 0.8 and 1 mm, yet admit a lack of consistent clarity in its utility for prognosis and therapeutic value in tumors < 1 mm and leave the decision for undergoing the procedure up to the patient and treating physician. Recent studies have evaluated specific patient populations, tumor histopathologic characteristics, and gene expression profiling and their use in predicting SLN positivity. These data have given insight into improving the physician's ability to potentially predict SLN positivity, shedding light on if and when omission of SLN biopsy in specific patients based on clinicopathological characteristics might be appropriate. This review provides discussion and insight into these recent advancements.
    Keywords:  DecisionDx-Melanoma; Gene expression profiling; Melanoma; Metastatic melanoma; Sentinel lymph node biopsy
    DOI:  https://doi.org/10.1007/s10585-021-10089-9
  18. Br J Dermatol. 2021 Jun 06.
    Melanoma genomics: a state-of-the-art review of practical clinical applications.
    S Guhan, N Klebanov, H Tsao.
      Our collective understanding of melanoma genomics has rapidly expanded in the past decade, bringing great promise to patients affected with the most severe and aggressive cases of melanoma. In this review, we present the practical clinical impact of genetics and genomics on modern melanoma diagnosis and treatment. Characterization of somatic driver mutations, which can be used to distinguish different subtypes of melanoma such as nonacral cutaneous melanoma (NACM), desmoplastic melanoma (DM), acral melanoma (AM), mucosal melanoma (MM) and uveal melanoma (UM), has led to the development of many targeted therapies against these tumours. Although targeted therapies exist for certain mutations, such as BRAF and KIT, other genotypes respond to newer-generation immune therapies such as immune checkpoint inhibitors. Epigenetics also plays a critical role in melanoma pathogenesis and drug resistance, holding promise for new treatment avenues. In this review, special attention is placed on clinical trials and translational research, especially novel genomic tests aimed to benefit patients on an individualized level in the current emerging era of personalized therapy.
    DOI:  https://doi.org/10.1111/bjd.20421
  19. J Immunother Cancer. 2021 Jun;pii: e002057. [Epub ahead of print]9(6):
    Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma.
    Yousef Zakharia, Robert R McWilliams, Olivier Rixe, Joseph Drabick, Montaser F Shaheen, Kenneth F Grossmann, Ravindra Kolhe, Rafal Pacholczyk, Ramses Sadek, Lucinda L Tennant, Christopher M Smith, Eugene P Kennedy, Charles J Link, Nicholas N Vahanian, Jiayi Yu, Steven S Shen, Erik L Brincks, Gabriela R Rossi, David Munn, Mohammed Milhem.
       BACKGROUND: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.
    METHODS: Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.
    RESULTS: Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator's choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).
    CONCLUSION: In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.
    Keywords:  -Dioxygenase; 3; immunotherapy; indoleamine-pyrrole 2; melanoma
    DOI:  https://doi.org/10.1136/jitc-2020-002057
  20. Cancer Rep (Hoboken). 2021 Jun 09. e1380
    Impact of molecular testing in advanced melanoma on outcomes in a tertiary cancer center and as reported in a publicly available database.
    Maya Dimitrova, Min Jae Kim, Iman Osman, George Jour.
       BACKGROUND: In patients with advanced melanoma (MM), genomic profiling may guide treatment decisions in the frontline setting and beyond as specific tumor mutations can be treated with targeted therapy (TT). The range of panel sizes used to identify targetable mutations (TM) can range from a few dozen to whole exome sequencing (WES).
    AIM: We investigated the impact of panel size and mutation status on first-line treatment selection and outcomes in MM.
    METHODS AND RESULTS: We analyzed data for 1109 MM patients from three cohorts: 169 patients at NYULH and profiled with the 50 gene Ion Torrent panel (IT), 195 patients at MSKCC, profiled with the 400-gene MSK-IMPACT panel (MSK-I) and 745 patients at seven different sites profiled with WES. Data for cohorts 2 and 3 were extrapolated from the publicly available cBioPortal. Treatment information was available for 100%, 25%, and 0% of patients in cohort 1, 2, and 3, respectively. BRAF and NRAS were among the top five most commonly mutated genes in the IT and MSK-I, whereas for WES only BRAF was a top five mutation. There was no significant difference in OS for BRAF MUT patients treated with immune checkpoint inhibitors (ICI) vs TT in cohort 1 (P = .19), nor for BRAF MUT patients from cohort 1 treated with ICI vs those from cohort 2 treated with TT (P = .762).
    CONCLUSION: Public datasets provide population-level data; however, the heterogeneity of reported clinical information limits their value and calls for data standardization. Without evidence of clear clinical benefit of a larger panel size, there is a rationale for adopting smaller, more cost effective panels in MM.
    Keywords:  cancer genetics; melanoma; mutations; targeted therapy
    DOI:  https://doi.org/10.1002/cnr2.1380
  21. Hum Cell. 2021 Jun 11.
    Suppressive role of microRNA-130b-3p in ferroptosis in melanoma cells correlates with DKK1 inhibition and Nrf2-HO-1 pathway activation.
    Yangying Liao, Xiaomin Jia, Yi Ren, Zhuoga Deji, Yuzhen Gesang, Ning Ning, Hao Feng, Hong Yu, An Wei.
      Cell death pathways related to ferroptosis are implicated in the progression of melanoma. Emerging data reporting the upregulation of microRNA (miR)-130b-3p in melanoma indicate the potential implication of miR-130b-3p in this malignancy. Herein, we aimed to identify whether and how miR-130b-3p regulated ferroptosis in melanoma cells. Melanoma cells (A375, G-361) were treated with erastin or RSL3 to mimic ferroptosis in vitro. Viability, lipid peroxidation level and ferrous ion content in melanoma cells were then assessed in response to manipulation of miR-130b-3p expression. Luciferase assay was conducted to determine the binding of miR-130b-3p to Dickkopf1 (DKK1). Western blot assay was conducted to determine the expression of molecules related to nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. The results indicated that miR-130b-3p exerted an inhibitory role in erastin or RSL3-induced ferroptosis, evidenced by reductions in lipid peroxidation and ferrous ion content. By suppressing the expression of target gene DKK1, miR-130b-3p activated the Nrf2/HO-1 pathway, whereby repressing ferroptosis. miR-130b-3p blocked the antitumor activity of erastin. Further, in vitro findings were reproduced in an in vivo murine model. Together, these data suggest the potential of miR-130b-3p to inhibit ferroptosis in melanoma cells and the mechanism was related to DKK1-mediated Nrf2/HO-1 pathway.
    Keywords:  DKK1; Ferroptosis; Iron accumulation; Lipid peroxidation; Melanoma; Nrf2/HO-1 pathway; microRNA-130b
    DOI:  https://doi.org/10.1007/s13577-021-00557-5
  22. Oncol Lett. 2021 Jul;22(1): 566
    Effect of melanoma stem cells on melanoma metastasis.
    Qiliang Yin, Xiumin Shi, Shijie Lan, Haofan Jin, Di Wu.
      Cancer stem cells (CSCs) are involved in the metastatic process, the resistance of many types of cancer to therapeutic treatments and consequently the onset of recurrences. The CSC concept therefore significantly extends our understanding of melanoma biology. More recently, melanoma stem cells (MSCs) have been described in melanoma as expressing specific biomarkers. These primitive melanoma cells are not only capable of self-renewal and differentiation plasticity, but may also confer virulence via immune evasion and multidrug resistance, and potentially, via vasculogenic mimicry and transition to migratory and metastasizing derivatives. This review will present the specific biomarkers of MSCs, including CD133, ATP binding cassette subfamily B member 5, CD271, CD20 and aldehyde dehydrogenase, which can regulate the transduction of tumor-related signals. These signal molecules can reversely act on tumor cells and regulate tumor angiogenesis, leading to the occurrence of melanoma metastasis. Targeting these specific biomarkers could inhibit the progression of melanoma and may help the development of novel therapeutic strategies for melanoma.
    Keywords:  cancer stem cells; melanoma; melanoma stem cells; metastasis; targeted therapy
    DOI:  https://doi.org/10.3892/ol.2021.12827
  23. Cesk Slov Oftalmol. 2020 ;1(Ahead of print): 1-13
    Therapy of uveal melanoma A Review.
    Š Rusňák, L Hecová, Z Kasl, M Sobotová, L Hauer.
      The aim of intraocular melanoma therapy is to achieve local tumor control, reduce the risk of metastasis development, preserve the eyeball and possibly the visual function of the eye. The choice of therapeutic approach requires a comprehensive view and individual approach to each patient with uveal melanoma. Factors considered include local finding (location, tumor size and shape, tumor activity, central visual acuity, intraocular complications), age and the patients overall physical and psychological condition, as well as the patients wishes. The most widely used method of uveal melanoma treatment is radiotherapy. The effect of radiation is caused by the absorption of ionizing radiation energy, the effect of radiation on the cell is manifested by cell death (depletion), or by a cytogenetic information change (mutation). Brachytherapy uses scleral applicators with radionuclide - ruthenium (Ru-106) applicators dominate in Europe and iodine (I-125) applicators in the USA. In external radiotherapy, the source of ionizing radiation is outside the patients body. Both stereotactic radiosurgery and fractionated stereotactic radiotherapy are used. In the Czech Republic, treatment is carried out using Leksell gamma knife or CyberKnife, while proton therapy dominates in the world. The development of serious radiation complications (radiation retinopathy, neuropathy, neovascular glaucoma, toxic tumor syndrome, etc.) should be considered. Surgical therapy involves a variety of invasive procedures. Iridectomy is performed for iris melanoma. Anteriorly located choroidal melanomas and / or ciliary body melanomas can be resolved by transscleral resection (exoresection). For posterior choroidal melanomas, a combination of external tumor irradiation with pars plana vitrectomy is used. Enucleation is a method of choice in advanced tumors that cannot be effectively irradiated. Orbital exenteration is indicated in advanced tumors with extrabulbar spread or in relapsed tumor after previous enucleation.
    Keywords:  brachytherapy; endoressection; exoressection; radiotherapy; teleradiotherapy; uval melanoma; uveal melanoma
    DOI:  https://doi.org/10.31348/2020/10
  24. J Cell Mol Med. 2021 Jun 06.
    Up-regulation of KISS1 as a novel target of Let-7i in melanoma serves as a potential suppressor of migration and proliferation in vitro.
    Haider A Alkafaji, Ahmed Raji, Heshu S Rahman, Angelina O Zekiy, Ali Adili, Mohammadmahdi Jalili, Tahereh Hojjatipour, Angel Cid-Arregui, Navid Shomali, Saeed Tarzi, Rozita Tamjidifar, Ramin Heshmati, Faroogh Marofi, Morteza Akbari, Ali Hasanzadeh, Mina Deljavanghodrati, Mostafa Jarahian, Siamak Sandoghchian Shotorbani.
      Melanoma is a kind of skin cancer that is begun by the alteration of melanocytes. miRNAs are small non-coding RNA molecules that regulate a variety of biological processes. KISS1, the metastasis-suppressor gene, encodes kisspeptins which inhibits migration and proliferation of cancers. This study was aimed to determine the role of Let-7i and KISS1 in melanoma cell migration and proliferation. At first, the expression of Let-7i and KISS1 was determined in patients with melanoma. In the in vitro part of the study, Let-7i mimics were transfected and the impact of its restoration on target gene expression, proliferation, migration and apoptosis of SK-MEL-3 melanoma cell line was assessed by real-time PCR and Western blotting, MTT assay, wound-healing assay and flow cytometry, respectively. Besides, KISS1 inhibitor siRNA alone and along with Let-7i was transfected to determine their probable correlation. The results revealed that either Let-7i or KISS1 were down-regulated in patients with melanoma. The results obtained from the in vitro part of the study revealed that restoration of Let-7i reduced the expression of metastasis- and proliferation-related target genes. Moreover, it was revealed that up-regulation of Let-7i attenuated migration and proliferation capability of SK-MEL-3 cells. Besides, it was demonstrated that Let-7i restoration induced apoptosis in melanoma cells. More importantly, the KISS1 inhibitor caused a prominent cell migration and proliferation, attenuated by Let-7i re-expression. To sum up, the present study revealed the impressive role of Let-7i restoration along with its correlation with KISS1 on melanoma carcinogenicity which may be applicable in future in vivo studies.
    Keywords:  KISS1; Let-7i; apoptosis; melanoma; migration; proliferation
    DOI:  https://doi.org/10.1111/jcmm.16695
  25. J Am Acad Dermatol. 2021 Jun 08. pii: S0190-9622(21)01110-5. [Epub ahead of print]
    Is Melanoma Overdiagnosed? A Review of the Evidence.
    Sonal Muzumdar, Gloria Lin, Philip Kerr, Jane M Grant-Kels.
       BACKGROUND: Melanoma is one of the most commonly diagnosed malignancies in the United States (US) and is responsible for the majority of deaths from skin cancer.
    OBJECTIVE: Since the 1970s, the incidence of melanoma has risen appreciably while melanoma-specific mortality has remained stable. This has raised a debate about potential overdiagnosis of melanoma. Herein, we review temporal trends in melanoma incidence and mortality, and explore factors that may contribute to observed trends, including an aging US population, ultraviolet exposure, increased numbers of biopsies by dermatologists and physician extenders, skin cancer screenings, histopathology criteria, and historical underdiagnosis. Additionally, we discuss melanoma overdiagnosis and the extent to which it may contribute to current trends.
    METHODS: Review of the literature RESULTS: Several factors may contribute to increased melanoma incidence including an aging population, ultraviolet exposure, increased skin biopsies, skin cancer screenings, histopathologic criteria, historical underdiagnosis and current overdiagnosis.
    LIMITATIONS: Further studies are required to determine exactly which tumors are being overdiagnosed, and how clinicians should adjust their practice to improve patient outcomes.
    CONCLUSION: The rise in melanoma incidence observed since the 1970s is likely multifactorial.
    Keywords:  aging; biopsies; histopathology; melanoma; melanoma pandemic; overdiagnosis; public health; skin cancer screenings; ultraviolet exposure
    DOI:  https://doi.org/10.1016/j.jaad.2021.06.010
  26. Commun Biol. 2021 Jun 07. 4(1): 695
    Functional in vivo characterization of sox10 enhancers in neural crest and melanoma development.
    Rebecca L Cunningham, Eva T Kramer, Sophia K DeGeorgia, Paula M Godoy, Anna P Zarov, Shayana Seneviratne, Vadim Grigura, Charles K Kaufman.
      The role of a neural crest developmental transcriptional program, which critically involves Sox10 upregulation, is a key conserved aspect of melanoma initiation in both humans and zebrafish, yet transcriptional regulation of sox10 expression is incompletely understood. Here we used ATAC-Seq analysis of multiple zebrafish melanoma tumors to identify recurrently open chromatin domains as putative melanoma-specific sox10 enhancers. Screening in vivo with EGFP reporter constructs revealed 9 of 11 putative sox10 enhancers with embryonic activity in zebrafish. Focusing on the most active enhancer region in melanoma, we identified a region 23 kilobases upstream of sox10, termed peak5, that drives EGFP reporter expression in a subset of neural crest cells, Kolmer-Agduhr neurons, and early melanoma patches and tumors with high specificity. A ~200 base pair region, conserved in Cyprinidae, within peak5 is required for transgenic reporter activity in neural crest and melanoma. This region contains dimeric SoxE/Sox10 dimeric binding sites essential for peak5 neural crest and melanoma activity. We show that deletion of the endogenous peak5 conserved genomic locus decreases embryonic sox10 expression and disrupts adult stripe patterning in our melanoma model background. Our work demonstrates the power of linking developmental and cancer models to better understand neural crest identity in melanoma.
    DOI:  https://doi.org/10.1038/s42003-021-02211-0
  27. Pharmgenomics Pers Med. 2021 ;14 667-681
    Identification and Validation of Immune-Related lncRNA Signature as a Prognostic Model for Skin Cutaneous Melanoma.
    Shuai Ping, Siyuan Wang, Jinbing He, Jianghai Chen.
       Purpose: Skin cutaneous melanoma (SKCM) is the most aggressive skin cancer that results in high morbidity and mortality rate worldwide. Immune-related long non-coding RNAs (IRlncRs) play an important role in regulating gene expression in tumors. Therefore, in this study, we aimed to identify IRlncRs signature that could predict prognosis and therapeutic targets for melanoma irrespective of the gene expression levels.
    Methods: RNA-sequencing data were obtained from The Cancer Genome Atlas (TCGA). IRlncRs were identified using co-expression analysis and recognized using univariate analysis. The impact of IRlncRs on survival was analyzed using a modified least absolute shrinkage and selection operator (Lasso) regression model. A 1-year survival receiver operating characteristic curve was constructed, and the area under the curve was calculated to identify the optimal cut-off point to distinguish between high and low-risk groups in patients with SKCM. Furthermore, integrative analysis was performed to identify the impact of clinicopathological features, chemotherapeutic treatment, tumor-infiltrating immune cells, and mutant genes on survival.
    Results: A total of 28 IRlncRs significantly associated with survival were identified. Seventeen IRlncRs pairs were used to build a survival risk model that could be used to distinguish between low and high-risk groups. The high-risk group was negatively associated with tumor-infiltrating immune cells and had a higher half inhibitory centration for chemotherapeutic agents such as cisplatin and vinblastine. Additionally, the high-risk group had a positive correlation with the expression of specific mutant genes such as BRAF and KIT.
    Conclusion: Our findings demonstrate that some IRlncRs have a significant correlation with survival and therapeutic targets for SKCM patients and may provide new insight into the clinical diagnosis and treatment strategies for SKCM patients.
    Keywords:  immune-related gene; long non-coding RNA signature; melanoma; prognosis; the cancer genome atlas
    DOI:  https://doi.org/10.2147/PGPM.S310299
  28. Oncol Rep. 2021 Aug;pii: 158. [Epub ahead of print]46(2):
    The role of immunotherapy and molecular‑targeted therapy in the treatment of melanoma (Review).
    Paulina Stachyra-Strawa, Marzanna Ciesielka, Michał Janiszewski, Ludmiła Grzybowska-Szatkowska.
      Skin melanomas are malignant neoplasms originating from neuroectodermal melanocytes. Compared to other neoplasms, melanomas have a high rate of growth. Their incidence is highest in Australia and New Zealand, in high‑income European countries (Switzerland, Norway, Sweden) and in the US. In Poland, the standardized incidence rate is approximately 5/100,000. Melanomas are typically highly radioresistant and chemoresistant. Before the era of immunotherapy, inoperable lesions were treated using chemotherapy based mainly on dacarbazine, temozolomide or fotemustine, which did not yield the expected results in terms of extending survival time or improving patient comfort. Therefore, there has emerged a need to seek other solutions. In most cases, the use of immunological treatment or targeted therapy has had a positive impact on survival time and relapse‑free survival. However, these periods are still relatively short, hence the need for further research and improvement of treatment. The most promising strategies appear to be antibodies that block programmed death receptor‑1 (PD‑1) and programmed death receptor ligand‑1 (PD‑L1) molecules, anti‑CTLA4 antibodies (cytotoxic T‑lymphocyte antigen 4) and therapy with BRAF and MEK inhibitors.
    Keywords:  BRAF inhibitors; MEK inhibitors; PD‑1; PD‑L1; immunotherapy; melanoma
    DOI:  https://doi.org/10.3892/or.2021.8109
  29. Future Med Chem. 2021 Jun 07.
    Development and in vivo evaluation of fused benzazole analogs of anti-melanoma agent HA15.
    Antoine Millet, Mauro Safir Filho, Nedra Hamouda-Tekaya, Elisa Cavazza, Patricia Abbe, Johanna Rüdiger, Magali Plaisant, Julie Mayen, Stéphane Rocchi, Cyril Ronco, Rachid Benhida.
      Background: In line with our recent discovery of an efficient anticancer thiazolebenzenesulfonamide framework HA15 (1) based on a remarkable endoplasmic reticulum stress inducement mode of action, we report herein a series of innovative constrained HA15 analogs, featuring four types of bicylic derivatives. Results: The structure-activity relationship analysis, using a cell line assay, led us to identify a novel version of HA15: a new benzothiazole derivative (10b) exhibiting important anti-melanoma effect against sensitive and resistant melanoma cells. Meanwhile, compound 10b induced a significant tumor growth inhibition in vivo with no apparent signs of toxicity. Conclusion: These results consistently open new directions to improve and develop more powerful anticancer therapeutics harboring this type of fused framework.
    Keywords:  HA15; anti-melanoma agent; antineoplastic activity; benzazole derivatives; mice xenografts
    DOI:  https://doi.org/10.4155/fmc-2021-0001
  30. Front Oncol. 2020 ;10 586085
    FUT8-AS1 Inhibits the Malignancy of Melanoma Through Promoting miR-145-5p Biogenesis and Suppressing NRAS/MAPK Signaling.
    Xiang-Jun Chen, Sha Liu, Dong-Mei Han, De-Zhi Han, Wei-Jing Sun, Xiao-Chun Zhao, Jun-Qing Liang, Li Yu.
      Melanoma is the major lethal skin malignancy. However, the critical molecular drivers governing melanoma progression and prognosis are still not clear. By analyzing The Cancer Genome Atlas (TCGA) data, we identified FUT8-AS1 as a prognosis-related long non-coding RNA (lncRNA) in melanoma. We further confirmed that FUT8-AS1 is downregulated in melanoma. Reduced expression of FUT8-AS1 is correlated with aggressive clinical factors and inferior overall survival. Using in vitro functional assays, our findings demonstrated that ectopic expression of FUT8-AS1 represses melanoma cell proliferation, migration, and invasion. FUT8-AS1 silencing promotes melanoma cell proliferation, migration, and invasion. Furthermore, in vivo functional assays demonstrated that FUT8-AS1 represses melanoma growth and metastasis. Mechanistically, FUT8-AS1 was found to bind NF90, repress the interaction between NF90 and primary miR-145 (pri-miR-145), relieve the repressive roles of NF90 on mature miR-145-5p biogenesis, and thus promote miR-145-5p biogenesis and upregulate mature miR-145-5p level. The expression of FUT8-AS1 is positively correlated with miR-145-5p in melanoma tissues. Via upregulating miR-145-5p, FUT8-AS1 reduces the expression of NRAS, a target of miR-145-5. FUT8-AS1 further represses MAPK signaling via downregulating NRAS. Functional rescue assays demonstrated that inhibition of miR-145-5p reverses the tumor suppressive roles of FUT8-AS1 in melanoma. The oncogenic roles of FUT8-AS1 silencing are also blocked by MAPK signaling inhibitor MEK162. In conclusion, these findings demonstrate that FUT8-AS1 exerts tumor suppressive roles in melanoma via regulating NF90/miR-145-5p/NRAS/MAPK signaling axis. Targeting FUT8-AS1 and its downstream molecular signaling axis represent promising therapeutic strategies for melanoma.
    Keywords:  FUT8-AS1; MAPK signaling; NF90; malignancy; melanoma; microRNA biogenesis
    DOI:  https://doi.org/10.3389/fonc.2020.586085
  31. J Invest Dermatol. 2021 Jun 08. pii: S0022-202X(21)01319-1. [Epub ahead of print]
    UDP-GlcNAc-1-phosphotransferase is a clinically important regulator of human and mouse hair pigmentation.
    Stephan Tiede, Jennifer E Hundt, Ralf Paus.
      UDP-GlcNAc-1-phosphotransferase, a product of two separate genes (GNPTAB, GNPTG), is essential for sorting and transport of lysosomal enzymes to lysosomes. GNPTAB gene defects cause extracellular missorting of lysosomal enzymes resulting in lysosomal storage diseases, namely mucolipidosis (ML) type II, which is associated with hair discoloration. Yet, the physiological functions of GNPTAB in the control of hair follicle (HF) pigmentation remain unknown. To elucidate these, we have silenced GNPTAB- in organ-cultured human HFs as a human ex vivo-model for MLII. GNPTAB-silencing profoundly inhibited intrafollicular melanin production, the correct sorting of melanosomes, tyrosinase activity and HMB45 expression in the HF pigmentary unit, and altered HF melanocyte morphology in situ. In isolated primary human HF melanocytes, GNPTAB knockdown significantly reduced melanogenesis, tyrosinase activity, and correct tyrosinase protein sorting as well as proopiomelanocortin (POMC) expression, and caused the expected lysosomal enzyme missorting in vitro. Moreover, transgenic mice overexpressing an inserted missense-mutation corresponding to human MLII showed significantly reduced HF pigmentation, thus corroborating the in vivo relevance of our ex vivo and in vitro findings in the human system. This identifies GNPTAB as a clinically important enzymatic control of human HF pigmentation, likely by directly controlling tyrosinase sorting and POMC-transcription in HF melanocytes.
    DOI:  https://doi.org/10.1016/j.jid.2021.04.028
  32. J Am Acad Dermatol. 2021 Jun 02. pii: S0190-9622(21)01044-6. [Epub ahead of print]
    Association between income and suspected non-melanoma and melanoma skin cancers among participants of the American Academy of Dermatology's SPOT Skin Cancer® screening program - A cross-sectional analysis.
    Derek Beaulieu, David X Gao, Susan M Swetter, Elena B Hawryluk, Alan C Geller.
      
    Keywords:  American Academy of Dermatology; SPOT Skin Cancer® screening program; basal cell carcinoma; income; melanoma; non-melanoma skin cancer; public health; screening; skin cancer; skin examination; socioeconomic status; squamous cell carcinoma
    DOI:  https://doi.org/10.1016/j.jaad.2021.05.048
  33. Mol Clin Oncol. 2021 Jul;15(1): 141
    Evaluation of 2-methoxyestradiol serum levels as a potential prognostic marker in malignant melanoma.
    Igor Hrgovic, Johannes Kleemann, Monika Doll, Carmen Loquai, Florian Weid, Frank Louwen, Nadja Zoeller, Stefan Kippenberger, Roland Kaufmann, Markus Meissner.
      Experimental findings indicated that 2-methoxyestradiol (2-ME), an endogenous metabolite of 17β-estradiol, may exhibit anti-tumorigenic properties in various types of tumour, such as melanoma and endometrial carcinoma. In patients with endometrial cancer, the serum levels of 2-ME are decreased compared with those in healthy controls, and this finding has been associated with a poor outcome. The aim of the present study was to examine whether the serum levels of 2-ME are decreased in patients with melanoma, and whether this decrease may be correlated with disease stage and, therefore, serve as a prognostic indicator. ELISA was used to detect serum levels of 2-ME in patients with stage I-IV malignant melanoma (MM). A cohort of 78 patients with MM was analysed, along with 25 healthy controls, among whom 15 were women in the second trimester of pregnancy (positive control). As expected, significantly elevated levels of serum 2-ME were observed in pregnant control patients compared with those in patients with MM and healthy controls. There was no observed correlation between 2-ME serum levels in patients with MM and disease stage, tumour thickness, lactate dehydrogenase or S100 calcium-binding protein B levels. In addition, the 2-ME levels of patients with MM did not differ significantly from those of normal healthy controls. Overall, the findings of the present study indicated that the 2-ME serum levels in patients with MM were not decreased, and there was no correlation with early- or advanced-stage disease. Therefore, in contrast to published results on endometrial cancer, endogenous serum 2-ME levels in MM were not found to be correlated with tumour stage and did not appear to be a suitable prognostic factor in MM.
    Keywords:  2-methoxyestradiol; S100 calcium-binding protein B; lactate dehydrogenase; melanoma; prognostic factor; stage
    DOI:  https://doi.org/10.3892/mco.2021.2303
  34. Onco Targets Ther. 2021 ;14 3487-3501
    Acetone Extract of Cornus officinalis Leaves Exerts Anti-Melanoma Effects via Inhibiting STAT3 Signaling.
    Ruiqi Xu, Mengnan Zeng, Yuanyuan Wu, Shengchao Wang, Beibei Zhang, Jingke Zhang, Yuxuan Kan, Benke Li, Bing Cao, Xiaoke Zheng, Weisheng Feng.
       Purpose: This research aims to investigate the intervention and mechanism of 50% acetone extract of C. officinalis leaves (SZYY) on melanoma xenografts.
    Patients and Methods: Tumor size and cardiac function were measured via ultrasound. The accumulation of 2-deoxy-D-glucose (2-DG) in tumor tissue was examined with near-infrared in vivo imaging. Flow cytometry was performed to assess apoptosis and reactive oxygen species (ROS) levels in tumor and immune cells in spleen. The levels of inflammatory cytokines in serum were detected by cytometric bead array. The expression of proliferation-, apoptosis-, and angiogenesis-related proteins in tumor cells was measured to evaluate the underlying mechanisms. Subsequently, the effects of four compounds separated from SZYY on the proliferation and migration of A375 cells and STAT3 signaling were examined. The peak identification and contents of the four components were performed via high-performance liquid chromatography (HPLC). Finally, we evaluated the inhibitory effects of STAT3 overexpression on the cytotoxic activity of four constituents in A375 cells.
    Results: SZYY inhibited the growth and glycolysis of melanoma xenograft in mice, improved cardiac function, increased the percentages of macrophages, neutrophils, and lymphocytes in spleen, reduced the levels of IL-6, IL-17A, TNF-α, and IFN-γ in serum, promoted apoptosis and oxidative stress in tumor tissues, and inhibited STAT3 phosphorylation and expression of angiogenic factors. Chemical analysis showed that SZYY is rich in loganin, rutin, triohimas C, and triohimas D, which all could restrain the proliferation and migration of A375 cells and inhibit the phosphorylation and nuclear translocation of STAT3. Moreover, STAT3 overexpression could diminish the cytotoxic activity of four compounds on A375 cells.
    Conclusion: SZYY could exert anti-melanoma effects via inhibiting STAT3 signaling to induce apoptosis and inhibit tumor angiogenesis. Its active ingredients might be loganin, rutin, triohimas C, and triohimas D.
    Keywords:  Cornus officinalis; STAT3; angiogenesis; apoptosis; melanoma
    DOI:  https://doi.org/10.2147/OTT.S308371
  35. Cancer Immunol Res. 2021 Jun 08. pii: canimm.CIR-20-0814-E.2020. [Epub ahead of print]
    Viral Molecular Mimicry Influences the Antitumor Immune Response in Murine and Human Melanoma.
    Jacopo Chiaro, Henna H E Kasanen, Thomas Whalley, Cristian Capasso, Mikaela Grönholm, Sara Feola, Karita Peltonen, Firas Hamdan, Micaela Hernberg, Siru Mäkelä, Hanna Karhapää, Paul E Brown, Beatriz Martins, Manlio Fusciello, Erkko O Ylösmäki, Dario Greco, Anna S Kreutzman, Satu Mustjoki, Barbara Szomolay, Vincenzo Cerullo.
      Molecular mimicry is one of the leading mechanisms by which infectious agents can induce autoimmunity. Whether a similar mechanism triggers an antitumor immune response is unexplored, and the role of antiviral T cells infiltrating the tumor has remained anecdotal. To address these questions, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we demonstrated that, in mice, pre-existing immunity toward specific viral epitopes enhanced the efficacy of cancer immunotherapy via molecular mimicry in different settings. To understand whether this mechanism could partly explain immunotherapy responsiveness in humans, we analyzed a cohort of melanoma patients undergoing anti-PD1 treatment who had a high IgG titer for cytomegalovirus (CMV). In this cohort of patients, we showed that high levels of CMV-specific antibodies were associated with prolonged progression-free survival and found that, in some cases, PBMCs could cross-react with both melanoma and CMV homologous peptides. Finally, TCR sequencing revealed expansion of the same CD8+ T-cell clones when PBMCs were expanded with tumor- or homologous viral peptides. In conclusion, we have demonstrated that pre-existing immunity and molecular mimicry could influence the response to immunotherapies. In addition, we have developed a free online tool that can identify tumor antigens and neoantigens highly similar to pathogen antigens, in order to exploit molecular mimicry and cross-reactive T cells in cancer vaccine development.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-20-0814
  36. Case Rep Oncol Med. 2021 ;2021 8845063
    Posterior Reversible Encephalopathy Syndrome (PRES) and Drug-Induced Hypersensitivity Syndrome (DIHS) following Immunotherapy and BRAF/MEK Inhibition with Continued Response in Metastatic Melanoma.
    J M Sabile, D J Grider, K A Prickett, H Li, P V Mallidi.
      Background. The role of immunotherapy continues to evolve across both solid and hematologic malignancies. However, while use of immunotherapy has increased via the advent of checkpoint inhibition, chimeric antigen receptors, and vaccines against malignant cells, there remains uncertainty regarding the recognition and management of delayed immune-related reactions and post treatment immune-related sensitivity to subsequent medications, such as BRAF/MEK kinase inhibitors. Furthermore, it is unclear how immunotherapy may alter the adverse effect profile and efficacy of subsequent lines of treatment. Case Presentation. Discussed is a patient with stage IV metastatic melanoma who failed first-line treatment with a combination of nivolumab and ipilimumab. He was then treated with BRAF/MEK kinase inhibition via Encorafenib and Binimetinib. Shortly thereafter, the patient developed posterior reversible encephalopathy syndrome (PRES) and a generalized pruritic rash that was biopsied with consideration toward drug reaction versus drug-induced hypersensitivity syndrome (DIHS), formerly called drug reaction with eosinophilia and systemic symptoms (DRESS). The BRAF/MEK combination was held and steroid taper initiated with continued response even beyond conclusion of the steroid taper. Discussion and Conclusions. This case highlights the diagnostic challenge presented by PRES and DIHS in the setting of immunotherapy and BRAF/MEK kinase inhibition for malignant melanoma. The clinical rationale for reinitiating therapy following severe immune reactions subsequent to immunotherapy in the setting of relapsed/refractory metastatic melanoma is discussed. Additionally, the durable response our patient experienced throughout the drug hold period and steroid taper and its clinical potential etiologies and applications are reviewed. As checkpoint inhibition and tyrosine-kinase inhibitors have become cornerstones of cancer therapy, larger studies and long-term observations are needed to investigate the risks and benefits across different sequences of therapy.
    DOI:  https://doi.org/10.1155/2021/8845063
  37. Front Cell Dev Biol. 2021 ;9 677944
    Spatiotemporal Analysis of B Cell- and Antibody Secreting Cell-Subsets in Human Melanoma Reveals Metastasis-, Tumor Stage-, and Age-Associated Dynamics.
    Minyi Chen, Franziska Werner, Christine Wagner, Martin Simon, Erika Richtig, Kirsten D Mertz, Johannes Griss, Stephan N Wagner.
      Background: The role of tumor-associated B cells in human cancer is only starting to emerge. B cells typically undergo a series of developmental changes in phenotype and function, however, data on the composition of the B cell population in human melanoma are largely absent including changes during tumor progression and their potential clinical significance. Methods: In this study, we compared the number and distribution of six major B cell and antibody secreting cell subpopulations outside tertiary lymphoid structures in whole tumor sections of 154 human cutaneous melanoma samples (53 primary tumors without subsequent metastasis, 44 primary tumors with metastasis, 57 metastatic samples) obtained by seven color multiplex immunohistochemistry and automated tissue imaging and analysis. Results: In primary melanomas, we observed the highest numbers for plasmablast-like, memory-like, and activated B cell subtypes. These cells showed a patchy, predominant paratumoral distribution at the invasive tumor-stroma margin. Plasma cell-like cells were hardly detected, germinal center- and transitional/regulatory-like B cells not at all. Of the major clinicopathologic prognostic factors for primary melanomas, metastasis was associated with decreased memory-like B cell numbers and a higher age associated with higher plasmablast-like cell numbers. When we compared the composition of B cell subpopulations in primary melanomas and metastatic samples, we found a significantly higher proportion of plasma cell-like cells at distant metastatic sites and a higher proportion of memory-like B cells at locoregional than distant metastatic sites. Both cell types were detected mainly in the para- and intratumoral stroma. Conclusion: These data provide a first comprehensive and comparative spatiotemporal analysis of major B cell and antibody secreting cell subpopulations in human melanoma and describe metastasis-, tumor stage-, and age-associated dynamics, an important premise for B cell-related biomarker and therapy studies.
    Keywords:  human melanoma; memory B cells; multiplex immunohistochemistry; plasma cells; spatiotemporal dynamics; tumor microenvironment; tumor-associated B cells
    DOI:  https://doi.org/10.3389/fcell.2021.677944
  38. Cutis. 2021 Apr;107(4): E19-E26
    Treatment Delay in Melanoma: A Risk Factor Analysis of an Impending Crisis.
    Marcus L Elias, Ann M John, Spandana Maddukuri, Robert A Schwartz, W Clark Lambert.
      Risk factors associated with melanoma treatment delay (MTD) have been inadequately studied. To elucidate MTD associations based on patient and tumor characteristics, a retrospective cohort study was performed for cutaneous melanoma cases reported to the National Cancer Database (NCDB) between 2004 and 2015. We evaluated the number of days from diagnosis to treatment initiation, analyzing postponements more than 45 days as moderate MTD (mMTD) and postponements more than 90 days as severe MTD (sMTD). Greater MTD rates were independently associated with patients who are older than 50 years, female, nonwhite, not privately insured, and treated at an academic facility and who have more advanced tumor stage and head/neck primaries.
    DOI:  https://doi.org/10.12788/cutis.0235
  39. BMC Ophthalmol. 2021 Jun 05. 21(1): 250
    Acute exudative polymorphous vitelliform maculopathy during pembrolizumab treatment for metastatic melanoma: a case report.
    Ine Lambert, Giuseppe Fasolino, Gil Awada, Robert Kuijpers, Marcel Ten Tusscher, Bart Neyns.
       BACKGROUND: The use of immunomodulating therapy to treat various cancers has been on the rise and these immune checkpoint inhibitors are known to cause ocular side effects. In this article a case of acute exudative polymorphous vitelliform maculopathy (AEPVM) is reported which developed during a first line treatment with pembrolizumab.
    CASE PRESENTATION: A 54-year-old woman was referred because of blurry vision in both eyes with a yellow spot in the central visual field of the left eye. These symptoms started after four treatments with pembrolizumab (a monoclonal antibody against the programmed cell death receptor-1) for a metastatic recurrent vaginal mucosal melanoma. Her best corrected visual acuity was 10/10 in both eyes with a correction of + 2.00 bilaterally. There were no inflammatory findings in the anterior segment or the vitreous. Fundoscopy revealed an attenuation of the foveal reflex with subtle yellow-white subretinal macular deposits (vitelliform lesions) in both eyes. Fluorescein angiography did not show staining or leakage in the mid-phase, neither a late staining. Spectral-domain optical coherence tomography of the macula illustrated bilateral neurosensory retinal detachment with a thick, highly reflective band at the outer photoreceptor segment. En face structural OCT at the level of the photoreceptors showed focal areas of increased signal corresponding to hyperreflective vitelliform material. The treatment with pembrolizumab was ceased immediately. During the following visits we slowly saw an improvement of the neurosensory retinal detachment. After almost four months a total resolution of the subretinal fluid was visualized in both eyes without the use of additional treatment, though the vitelliform deposits persisted.
    CONCLUSIONS: The development of AEPVM in melanoma patients could be triggered by treatment with Pembrolizumab. Pembrolizumab has the potential to disturb indirectly the retinal pigment epithelium homeostasis with accumulation of lipofuscin deposits and subretinal fluid, both signs of AEPVM.
    Keywords:  Acute exudative polymorphous vitelliform maculopathy; Immune checkpoint inhibitors; Immune related adverse event; Pembrolizumab
    DOI:  https://doi.org/10.1186/s12886-021-02011-4
  40. Cancer Sci. 2021 Jun 07.
    Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors.
    Ikuko Hirai, Takeru Funakoshi, Hajime Kamijuku, Keitaro Fukuda, Mariko Mori, Masatoshi Sakurai, Yuya Koda, Jun Kato, Takehiko Mori, Naohide Watanabe, Shinobu Noji, Tomonori Yaguchi, Takashi Iwata, Shigeki Ohta, Tomonobu Fujita, Ryuji Tanosaki, Makoto Handa, Shinichiro Okamoto, Masayuki Amagai, Yutaka Kawakami.
      To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho-depleting non-myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low-dose IL-2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL-ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL-ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short-term partial response, one relatively long-stable disease, and one experienced disease progression. Whole-exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL-ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell-recruiting chemokines, as well as various immunosuppressive factors including TGF-β, VEGF, Wnt/β-catenin, and MAPK signaling and epithelial-to-mesenchymal transition, which might influence the efficacy of TIL-ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL-ACT. Further studies of immune-resistant mechanisms of TIL-ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431).
    Keywords:  Adoptive cell therapy; Immune checkpoint inhibitor; Melanoma; Tumor infiltrating lymphocytes; feasibility study
    DOI:  https://doi.org/10.1111/cas.15009
  41. Oncoimmunology. 2021 May 23. 10(1): 1927313
    Incidence, predictors, and survival impact of acute kidney injury in patients with melanoma treated with immune checkpoint inhibitors: a 10-year single-institution analysis.
    Maen Abdelrahim, Omar Mamlouk, Heather Lin, Jamie Lin, Valda Page, Noha Abdel-Wahab, Joshua Swan, Umut Selamet, Cassian Yee, Adi Diab, Wadi Suki, Ala Abudayyeh.
      Background: The incidence of renal immune-related adverse events (irAEs) is reported to be 3.8%, with varied definitions of acute kidney injury (AKI). This study reports a 10-year experience at MD Anderson Cancer Center of patients diagnosed with melanoma and treated with immune checkpoint inhibitors (ICIs) and evaluated the incidence of AKI, associated factors, and its association with overall survival. Methods: A retrospective chart review (2010-2019) of all patients with melanoma treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab was performed. All available serum creatinine data were extracted and used to calculate the estimated GFR (eGFR) using the CKD Epi equation, and to diagnose AKI using the two KDIGO (Kidney Disease: Improving Global Outcomes) criteria for defining stage I AKI in 1664 unique patients. Cumulative incidence rates of AKI after initiation of ICIs were calculated in the presence of death as a competing risk. The effects of covariates on the cumulative incidence function of AKI were evaluated in a univariant and multivariable analysis. Overall survival was estimated by Kaplan-Meier method in accordance to the occurrence of AKI. Results: The incidence of AKI by definitions 1a and 1b were 3.49% and 3.33%, respectively. After adjudication, AKI attributable to ICI was 58% and 65% of the overall incidence of AKI in each definition respectively. Increasing age was associated with decreased risk of AKI. Asian race was associated with a higher risk of AKI. Comorbidities were not associated with increased risk of AKI while use of proton pump inhibitors (PPI), ipilimumab or ICI combinations were significantly associated with AKI. AKI was not significantly associated with overall survival. Immune-related adverse events (irAEs) occurred in 30% of patients with AKI but their incidence was not different in patients with AKI attributable to ICI versus other AKI. Conclusions: In a large population of patients with melanoma treated with ICIs, an accurate documentation of AKI in setting of ICI use and predictors associated is presented. AKI following ICI use is infrequent, not associated with mortality, and associated with the use of ipilimumab, ICI combinations and PPIs.
    Keywords:  Acute kidney injury; immune checkpoint inhibitor; melanoma; survival
    DOI:  https://doi.org/10.1080/2162402X.2021.1927313
  42. Exp Ther Med. 2021 Aug;22(2): 797
    Updates and new medical treatments for vitiligo (Review).
    David Emmanuel Kubelis-López, Natalia Aranza Zapata-Salazar, Salvador Luis Said-Fernández, Celia Nohemí Sánchez-Domínguez, Mauricio Andrés Salinas-Santander, Herminia Guadalupe Martínez-Rodríguez, Osvaldo Tomás Vázquez-Martínez, Uwe Wollina, Torello Lotti, Jorge Ocampo-Candiani.
      Vitiligo is a multifactorial disease characterized by the loss of skin pigment, which results in achromic macules and patches. There are currently several medical treatments available, which aim to arrest progression and induce skin repigmentation. These treatments alone or combined have exhibited varying degrees of pigmentation, and the majority are safe and effective. All therapies for vitiligo are limited, and no known treatment can consistently produce repigmentation in all patients. Individualized treatment is appropriate according to the location, clinical presentation and the presence of disease activity. The present review summarizes the medical treatments available for vitiligo: Systemic and topic pharmacological therapies, physical and depigmentation treatments. Several treatments are still underway and have not yet been approved. However, due to the promising preliminary results, these are also mentioned in the present review.
    Keywords:  combined modality therapy; immunosuppressive agents; phototherapy; skin lightening preparations; therapy; vitiligo
    DOI:  https://doi.org/10.3892/etm.2021.10229
  43. Cell Prolif. 2021 Jun 08. e13013
    Dermal papilla cells and melanocytes response to physiological oxygen levels depends on their interactions.
    Carla M Abreu, Rui L Reis, Alexandra P Marques.
       BACKGROUND: Human dermal papilla (DP) cells and melanocytes (hMel) are central players in hair growth and pigmentation, respectively. In hair follicles (HFs), oxygen (O2 ) levels average 5%, being coupled with the production of reactive oxygen species (ROS), necessary to promote hair growth.
    MATERIALS AND METHODS: DP cell and hMel proliferation and phenotype were studied under physiological (5%O2 , physoxia) or atmospheric (21%O2 , normoxia) oxygen levels. hMel-DP cells interactions were studied in indirect co-culture or by directly co-culturing hMel with DP spheroids, to test whether their interaction affected the response to physoxia.
    RESULTS: Physoxia decreased DP cell senescence and improved their secretome and phenotype, as well as hMel proliferation, migration, and tyrosinase activity. In indirect co-cultures, physoxia affected DP cells' alkaline phosphatase (ALP) activity but their signalling did not influence hMel proliferation or tyrosinase activity. Additionally, ROS production was higher than in monocultures but a direct correlation between ROS generation and ALP activity in DP cells was not observed. In the 3D aggregates, where hMel are organized around the DP, both hMel tyrosinase and DP cells ALP activities, their main functional indicators, plus ROS production were higher in physoxia than normoxia.
    CONCLUSIONS: Overall, we showed that the response to physoxia differs according to hMel-DP cells interactions and that the microenvironment recreated when in direct contact favours their functions, which can be relevant for hair regeneration purposes.
    Keywords:  cellular interactions; dermal papilla cells; hair follicle; melanocytes; physoxia
    DOI:  https://doi.org/10.1111/cpr.13013
  44. Clin Transl Oncol. 2021 Jun 08.
    Physio-pathological effects of m6A modification and its potential contribution to melanoma.
    Y Liao, P Han, Y Zhang, B Ni.
      Methylation of N6-adenosine (m6A) is the most prevalent internal RNA modification and is especially common among the messenger RNAs. These m6A modifications regulate splicing, translocation, stability and translation of RNA through dynamic and reversible interactions with m6A-binding proteins, namely the writers, erasers and readers. RNA methyltransferases catalyze the m6A modifications, while demethylases reverse this methylation. Deregulation of the m6A modification process has been implicated in human carcinogenesis, including melanoma-which carries one of the highest mutant rates. In this review, we provide an up-to-date summary of m6A regulation and its biological impacts on normal and cancer cells, with emphasis on the deregulation of m6A modification and m6A regulators in melanoma. In addition, we highlight the prospective potential of exploiting m6A modification in the treatment of melanoma and non-cancer diseases.
    Keywords:  Melanoma; RNA modification; Tumor; m6A
    DOI:  https://doi.org/10.1007/s12094-021-02644-3
  45. Sci Rep. 2021 Jun 07. 11(1): 11980
    Propionic acid produced by Cutibacterium acnes fermentation ameliorates ultraviolet B-induced melanin synthesis.
    Hsin-Jou Kao, Yan-Han Wang, Sunita Keshari, John Jackson Yang, Shinta Simbolon, Chun-Chuan Chen, Chun-Ming Huang.
      Ultraviolet irradiation induces melanin accumulation, which can be reduced by the use of chemical whitening products. However, the associated safety concerns of such products have prompted the search for natural and harmless alternatives. This study aimed to identify a natural acidic formulation to reduce skin pigmentation. The metabolite propionic acid (CH3CH2COOH, PA) was the most abundant fatty acid in the filtrate from Pluronic F68 (PF68) fermentation of Cutibacterium acnes (C. acnes) and reduced the DOPA-positive melanocytes by significantly inhibiting cellular tyrosinase activity via binding to the free fatty acid receptor 2 (FFAR2). Moreover, 4 mM PA treatment did not alter melanocyte proliferation, indicating that it is an effective solution for hyperpigmentation, causing no cellular damage. The reduced DOPA-positive melanocytes and tyrosinase activity were also observed in mice ear skin tissue injected with a mixture of C. acnes and PF68, supporting that the inhibition of melanogenesis is likely to be mediated through fermentation metabolites from C. acnes fermentation using PF68 as a carbon source. Additionally, PA did not affect the growth of its parent bacteria C. acnes, hence is a potent fermentation metabolite that does not disrupt the balance of the skin microbiome.
    DOI:  https://doi.org/10.1038/s41598-021-91386-x
  46. Ann Surg Oncol. 2021 Jun 09.
    ASO Visual Abstract: Assessment of Frailty Can Guide Decision Making for Utilization of Sentinel Lymph Node Biopsy in Patients with Thick Melanoma.
    Avinash S Sharma, Jessica R Flynn, Katherine S Panageas, Armin Shahrokni, Amy L Tin, Danielle M Bello, Charlotte E Ariyan, Mary Sue Brady, Daniel G Coit, Edmund K Bartlett.
      
    DOI:  https://doi.org/10.1245/s10434-021-10237-1
  47. Dev Psychobiol. 2021 Jun 09.
    Socioeconomic factors, stress, hair cortisol, and white matter microstructure in children.
    Katrina R Simon, Emily C Merz, Xiaofu He, Pooja M Desai, Jerrold S Meyer, Kimberly G Noble.
      Socioeconomic disadvantage has been linked to increased stress exposure in children and adults. Exposure to stress in childhood has been associated with deleterious effects on cognitive development and well-being throughout the lifespan. Further, exposure to stress has been associated with differences in brain development in children, both in cortical and subcortical gray matter. However, less is known about the associations among socioeconomic disadvantage, stress, and children's white matter development. In this study, we investigated whether socioeconomic disparities would be associated with differences in white matter microstructure in the cingulum bundle, as has been previously reported. We additionally investigated whether any such differences could be explained by differences in stress exposure and/or physiological stress levels. White matter tracts were measured via diffusion tensor imaging in 58 children aged 5-9 years. Results indicated that greater exposure to stressful life events was associated with higher child hair cortisol concentrations. Further, physiological stress, as indexed by hair cortisol concentrations, were associated with higher fractional anisotropy in the cingulum bundle. These results have implications for better understanding how perceived and physiological stress may alter neural development during childhood.
    Keywords:  child; cortisol; diffusion-weighted imaging; neurodevelopment; socioeconomic status; stress
    DOI:  https://doi.org/10.1002/dev.22147
  48. J Invest Dermatol. 2021 Jun 05. pii: S0022-202X(21)01324-5. [Epub ahead of print]
    RIP1-mediated necroptosis facilitates oxidative stress-induced melanocyte death offering insight into vitiligo.
    Bowei Li, Xiuli Yi, Tongtian Zhuang, Shaolong Zhang, Shuli Li, Yuqi Yang, Tingting Cui, Jiaxi Chen, Yuqian Chang, Tianwen Gao, Chunying Li, Ling Liu.
      Vitiligo is a common depigmentation disease characterized by the melanocyte death which is attributed to various mechanisms such as apoptosis and autoimmune destruction. However, whether necroptosis, a newly discovered way of cell death, plays a key role in the pathogenesis of vitiligo is still elusive has not been well studied. In this study, we found that necroptosis markers including phosphorylated receptor-interacting protein 3 (p-RIP3) and phosphorylated mixed lineage kinase domain-like protein (p-MLKL) were positive in melanocytes from vitiligo perilesional skins, which supported the existence of necroptosis in vitiligo. Furthermore, the expression of receptor-interacting protein 1 (RIP1) was remarkably upregulated in melanocytes treated with hydrogen peroxide (H2O2). Then, RIP1 intervention suppression and MLKL deficiency could significantly enhanced resistance of melanocytes to H2O2-induced necroptosis. Mechanistically, we confirmed that RIP1 and RIP3 could form necrosomes under oxidative stress and further trigger p-MLKL translocation to the cell membrane, which led to the destruction of melanocytes. Finally, we demonstrated that RIP1-mediated generation of mitochondrial reactive oxygen species (ROS) contributed to the necrosome formation in melanocytes. Collectively, our study confirms necroptosis significantly facilitates oxidative stress-induced melanocyte death via the RIP1 signaling pathway, offering insight into vitiligo.
    Keywords:  RIP1; necroptosis; oxidative stress; vitiligo
    DOI:  https://doi.org/10.1016/j.jid.2020.06.042
  49. N Engl J Med. 2021 Jun 10. 384(23): 2229-2240
    Recent Advances in the Treatment of Melanoma.
    Brendan D Curti, Mark B Faries.
      
    DOI:  https://doi.org/10.1056/NEJMra2034861
  50. JAMA Dermatol. 2021 Jun 09.
    Barriers to Physician-Based Skin Examinations for Adolescent and Young Adult Survivors of Melanoma in the Project Forward Study.
    Katherine Y Wojcik, Kimberly A Miller, Ashley Wysong, Ann S Hamilton, Michael R Cousineau, Myles G Cockburn, Joel E Milam.
      
    DOI:  https://doi.org/10.1001/jamadermatol.2021.1850
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