bims-tuinly 2026-08-02 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–08–02
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

The Prognostic Role of CD8+ Tumor-Infiltrating Lymphocyte Density in Head and Neck Mucosal Melanoma.
Expression of LAG-3, TIM-3, and VISTA on Tumor-Infiltrating Lymphocytes in Advanced Laryngeal Squamous Cell Carcinoma and Their Association with CD8+ TIL Density.
Dual stimulation of CD40 and 41BB pathways during ex-vivo TIL expansion enhances CD8+ T cell expansion.
Convection-Enhanced Delivery of Tumor-Infiltrating Lymphocytes Enhances Intratumoral Distribution and Therapeutic Efficacy in an Orthotopic Rat Glioma Model.
Immunologic determinants of infusion products and the tumor microenvironment govern response to TIL therapy in advanced melanoma.
Arginase 2 Downregulation in High-Grade Prostate Adenocarcinoma and Its Spatial Inverse Association with Tumor-Infiltrating Lymphocytes.
Real-World Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma: Treatment Delivery, Immune Reconstitution, and Cardiac Monitoring During High-Dose IL-2.
Histopathological biomarkers of immunotherapy outcome in advanced colorectal cancer: a multicentre retrospective study.
Association of BRAF Mutation Status with Histopathological Characteristics and Survival Outcomes in Stage II-III Malignant Melanoma.
Prognostic Value of Morphological Characteristics and Immune Microenvironment in High-Grade Serous Cancer (HGSC).
Correction: HLA-G expression in non-small cell lung cancer: prognostic significance and interplay with PD-L1 and CD8+ tumor-infiltrating lymphocytes.
The evolution of cellular therapies in sarcoma: Breakthroughs, challenges, and future directions.
Spatial T lymphocyte infiltration into the primary melanoma tumor associates with survival.

Otolaryngol Head Neck Surg. 2026 Jul 28.

The Prognostic Role of CD8+ Tumor-Infiltrating Lymphocyte Density in Head and Neck Mucosal Melanoma.

Nicholas K Fung, Douglas Hartman, Diwakar Davar, Eric W Wang.

   OBJECTIVE: To explore the prognostic role of CD8+ tumor-infiltrating lymphocytes (TIL) density in head and neck mucosal melanoma (HNMM) using an automated, quantitative, immunohistochemistry-based methodology.
STUDY DESIGN: Retrospective cohort study.
SETTING: Single-institution, tertiary care hospital.
METHODS: Forty-five patients with primary HNMM treated between January 2002 and December 2021 at the University of Pittsburgh were included. For patients with ample primary tumor specimens, CD8+ TIL density was quantified using an automated image analysis algorithm on digitized slides. Receiver operating characteristic curves were used to delineate a biomarker cutoff. Survival analysis using the Kaplan-Meier method and Cox proportional hazards was performed with recurrence-free survival (RFS) and overall survival (OS) as endpoints.
RESULTS: Thirty-four patients had adequate pathologic specimens available for analysis. CD8+ TIL density threshold of 373.6 cells/mm2 best delineated patients based on survival outcomes. On log-rank testing, TIL high patients trended toward improved 5-year RFS (p = 0.06) and OS (p = 0.074) when compared to TIL low patients. Using multivariate analysis, high TIL density was significantly associated with improved RFS (hazard ratio [HR] (95% confidence interval [CI]): 0.17 (0.03-0.83), p = 0.028) but not improved OS (HR (95% CI): 0.48 (0.08-2.90), p = 0.4). Tumor characteristics such as advanced nodal staging (HR (95% CI): 13.2 (1.68-104), p = 0.014), and presence of metastatic disease (HR (95% CI): 48.2 (1.94-1196), p = 0.018) were associated with worsened RFS.
CONCLUSION: Automated, digital CD8+ TIL density enumeration is a reliable method of assessing TIL density in HNMM patients. High CD8+ TIL density is an independent factor associated with improved RFS and trended toward improved OS.

Keywords:  biomarker; head and neck mucosal melanoma; prognostication; sinonasal mucosal melanoma; tumor infiltrating lymphocytes; tumor microenvironment

DOI:  https://doi.org/10.1002/ohn.70344
Biomedicines. 2026 Jul 15. pii: 1587. [Epub ahead of print]14(7):

Expression of LAG-3, TIM-3, and VISTA on Tumor-Infiltrating Lymphocytes in Advanced Laryngeal Squamous Cell Carcinoma and Their Association with CD8+ TIL Density.

Erdoğan Özgür, Ayça Tan, Özlem Yersal, Görkem Eskiizmir, Esin Oktay.

  Background: Alternative immune checkpoints such as lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA) have emerged as potential modulators of tumor immune escape. However, their expression patterns and prognostic significance in advanced laryngeal squamous cell carcinoma (LSCC) remain insufficiently characterized. This study aimed to evaluate LAG-3, TIM-3, and VISTA expression on tumor-infiltrating lymphocytes (TILs), examine their association with CD8+ TIL density and clinicopathological features, and determine their impact on survival outcomes. Methods: In this retrospective observational cohort study, 132 patients who underwent total or partial laryngectomy for stage III-IV LSCC were included. Tissue microarrays were constructed using three 2 mm cores per case. Immunohistochemical expression of LAG-3, TIM-3, VISTA, and CD8 was assessed exclusively on TILs. Survival outcomes were analyzed using Kaplan-Meier and Cox proportional hazards models. Results: LAG-3, TIM-3, and VISTA positivity rates were 26.5%, 51.5%, and 53.8%, respectively. High CD8+ TIL density was observed in 69.7% of cases. Significant positive correlations were identified among checkpoint markers (all p < 0.05); VISTA positivity did not significantly correlate with CD8 infiltration (r = 0.149, p = 0.088). LAG-3 positivity was associated with lower thyroid cartilage invasion (p = 0.006). Kaplan-Meier analysis demonstrated no significant differences in overall survival (OS) or disease-free survival (DFS) according to checkpoint expression or CD8 status. In multivariable analysis, extranodal extension (HR = 2.719, p = 0.005) and thyroid cartilage invasion (HR = 1.970, p = 0.043) were independent predictors of worse OS. CD8 negativity showed a trend toward adverse OS (HR = 1.825, p = 0.084). None of the immune markers independently predicted DFS. Conclusions: In advanced surgically treated LSCC, LAG-3, TIM-3, and VISTA expression correlate with CD8+ TIL density but do not independently predict survival outcomes. These findings suggest that alternative immune checkpoint expression reflects immune engagement rather than intrinsic tumor aggressiveness and may hold greater predictive than prognostic relevance in LSCC.

Keywords:  CD8-positive T-lymphocytes; LAG-3; TIM-3; VISTA; immune checkpoints; laryngeal squamous cell carcinoma; prognosis; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/biomedicines14071587
bioRxiv. 2026 Jul 26. pii: 2026.07.22.740128. [Epub ahead of print]

Dual stimulation of CD40 and 41BB pathways during ex-vivo TIL expansion enhances CD8+ T cell expansion.

Renata Ariza Marques Rossetti, Matthew S Beatty, Junior Cianne, Johannes R Ali, Kylie Harris, Ahmed Ramadan, Michael Grant, Elena Martinez Planes, Jyllica Aurelio, Lilit Karapetyan, Ben Creelan, Shari Pilon-Thomas, Patrick Hwu, Vincent C Luca, Daniel Abate-Daga.

Background: Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated clinical efficacy in malignant melanoma; however, inefficient ex vivo expansion remains a major limitation. We previously showed that stimulation of tumor-infiltrating B cells via CD40-CD40L axis improves TIL expansion, and that direct activation of the 41BB-41BBL pathway on T cells enhances CD8⁺ T cell outgrowth. We hypothesized that adding simultaneous targeting of both pathways would augment the growth and activity of CD8+ cytotoxic T cells. We conducted a study with the objective of determining the feasibility of dual stimulation with human tumors as justification for a Phase I trial.
Methods: CD40L variants were generated by yeast display selection and evaluated for B cell binding and activation. The effects of CD40L variants on TIL expansion were evaluated using tumors derived from standard of care resections using fragment method. Based on these findings, a bi-specific molecule was designed and generated fusing a CD40L variant and 41BB to the N- and C-termini of a trimeric leucine zipper. The effects of the bi-specific molecule (termed CD40L EPC6 -41BBL) on TIL expansion were evaluated in TIL cultures derived from lung tumor and melanoma fragments. TIL phenotypes were assessed by flow cytometry, including high-dimensional FlowSOM analysis, and tumor reactivity by autologous tumor co-culture assays.
Results: Each of our engineered CD40L variants bound B cells and induced CD80/CD86 expression at levels comparable to wild-type CD40L. Supplementation of TIL cultures with CD40L variants increased the success rate of TIL expansion compared to control. We then developed a bi-specific CD40L EPC6 -41BBL molecule capable of binding to both B and T cells. Addition of CD40L EPC6 -41BBL significantly increased total TIL yield and improved expansion success rates in both lung tumor and melanoma cultures. In particular, CD40L EPC6 -41BBL promoted preferential expansion of CD8⁺ T cells. High-dimensional analysis revealed enrichment of CD8⁺ T cell clusters expressing CD39, CD69, TIM3, and CD56 in cultures supplemented with CD40L EPC6 -41BBL. Furthermore, treated cultures displayed increased frequencies of CD27⁺ CD4⁺ T cells. Functional assessment suggested a trend toward enhanced tumor reactivity in melanoma-derived TIL products expanded with CD40L EPC6 -41BBL.
Conclusions: Simultaneous stimulation of CD40 and 41BB pathways using a novel bi-specific molecule resulted in qualitative and quantitative enhancement of TIL products. These findings support dual targeting of tumor-infiltrating B cells and T cells as a promising strategy to optimize TIL manufacturing for adoptive cell therapy in Phase I trials.

DOI: https://doi.org/10.64898/2026.07.22.740128
Biomedicines. 2026 Jun 28. pii: 1466. [Epub ahead of print]14(7):

Convection-Enhanced Delivery of Tumor-Infiltrating Lymphocytes Enhances Intratumoral Distribution and Therapeutic Efficacy in an Orthotopic Rat Glioma Model.

Yuan Zhou, Liwen Zhu, Xinglei Liu, Chunxia Ji, Jiakai Yao, Di Chen, Yu Yao.

  Background: Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) is a potential strategy for glioma treatment, but effective intracranial delivery remains a major obstacle. Convection-enhanced delivery (CED) may improve local parenchymal coverage by bypassing the blood-brain barrier and using pressure-driven interstitial transport. Methods: We evaluated whether CED could improve the early intracerebral distribution and antitumor activity of ex vivo-expanded TILs in an orthotopic rat C6 glioma model. Expanded TILs were characterized as a CD3-enriched lymphocyte product with inducible effector function against C6 glioma cells in vitro. TILs were administered as either Control-TILs by Hamilton syringe-based conventional intratumoral injection or CED-TILs by catheter-based CED infusion using matched cell dose, volume, infusion rate, target coordinates, and dwell time. Intracerebral CD3+ T-cell coverage, tumor progression, and overall survival were assessed. Short-term safety was evaluated in a separate cohort of naïve rats receiving CED-PBS or CED-TILs. Results: CED-TILs produced broader early intraparenchymal CD3+ T-cell coverage than Control-TILs, particularly at distal sampling sites from the infusion tract. Under this single-dose regimen, CED-TILs were associated with reduced tumor progression, decreased Ki67 expression, increased apoptosis-associated signaling, and prolonged survival. In the short-term naïve safety cohort, CED-TILs did not produce overt neurologic, histologic, hematologic, or systemic toxicity within the observation window. Conclusions: These findings support CED-TILs as an early proof-of-concept locoregional delivery strategy that improves early spatial CD3+ T-cell coverage and is associated with antitumor activity in a rat glioma model.

Keywords:  adoptive cell therapy; convection-enhanced delivery; glioblastoma; immunotherapy; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/biomedicines14071466
Med. 2026 Jul 29. pii: S2666-6340(26)00234-5. [Epub ahead of print] 101231

Immunologic determinants of infusion products and the tumor microenvironment govern response to TIL therapy in advanced melanoma.

Lilit Karapetyan, Jin Xu, Kimberly Ward, Denise Kalos, Benjamin Schachner, Johannes Ali, Xiaofei Song, Joel Kuriakose, MacLean S Hall, Jamie Chau, Cheryl A Cox, Ayah N Al-Bzour, Rana Falahat, Matthew C Perez, John E Mullinax, Jonathan S Zager, Ricardo Gonzalez, Vernon K Sondak, Kenneth Y Tsai, Jane L Messina, Carlos Moran-Segura, Neale Lopez-Blanco, Anthony E Alleyne, Jonathan V Nguyen, Michael J Schell, Joseph Markowitz, Andrew S Brohl, Zeynep Eroglu, Ahmad A Tarhini, Nikhil I Khushalani, Patrick Hwu, James J Mulé, Amod A Sarnaik, Matthew S Beatty, Shari Pilon-Thomas.

   BACKGROUND: The immunologic features of tumor-infiltrating lymphocyte (TIL) infusion products and their interactions with the tumor microenvironment that govern clinical responses in metastatic melanoma remain incompletely characterized.
METHODS: We performed integrated immunophenotypic and spatial transcriptomic profiling of TIL infusion products and matched tumor microenvironments from patients treated on early-phase clinical trials.
RESULTS: The durable objective response rate was 36%, with a median progression-free survival of 8 months among patients treated with TIL therapy with or without additional therapies. Responders exhibited infusion products enriched for CD8+ T cells, stem-like memory subsets, and LAG-3-expressing CD8+ T cells, together with enhanced peripheral TIL persistence. The abundance of infused LAG-3+ TILs correlated with tumor reactivity and prolonged progression-free survival. Prior immune checkpoint inhibitor exposure was associated with reduced CD8+ stem cell memory T cell frequency and diminished co-stimulatory receptor expression, suggesting impaired TIL fitness. Tumors enriched for tertiary lymphoid structures and spatial immune programs characterized by antigen presentation, interferon signaling, and B cell activation were independently associated with clinical benefit.
CONCLUSIONS: These findings define an integrated framework linking TIL composition and the tumor microenvironment to therapeutic response and identify potential biomarkers and biological features that may guide patient selection and optimization of TIL therapy.
FUNDING: This work was funded by Iovance Biotherapeutics, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Melanoma Research Alliance, the Donald A. Adam Melanoma & Skin Cancer Center of Excellence, American Cancer Society-Leo and Anne Albert Charitable Foundation Research Scholar Grant, and Melanoma SPORE (P50CA168536).

Keywords:  LAG-3; T cell fitness; adoptive cell therapy; metastatic melanoma; spatial transcriptomics; tertiary lymphoid structures; translation to patients; tumor microenvironment; tumor-infiltrating lymphocyte therapy

DOI:  https://doi.org/10.1016/j.medj.2026.101231
Asian Pac J Cancer Prev. 2026 Jul 01. pii: 92292. [Epub ahead of print]27(7): 2713-2719

Arginase 2 Downregulation in High-Grade Prostate Adenocarcinoma and Its Spatial Inverse Association with Tumor-Infiltrating Lymphocytes.

Arif Budiman Kaharuddin, Muhammad Husni Cangara, Upik A Miskad, Syarifuddin Wahid, Djumadi Achmad, Berti Julian Nelwan.

   OBJECTIVE: The interaction between metabolic enzymes and the immune microenvironment in prostate cancer is still complex. This study aimed to examine the relationship between Arginase 2 (ARG2) expression and tumor-infiltrating lymphocytes (TILs) in prostate adenocarcinoma patients, as well as its correlation with histopathological grading, thereby elucidating immunometabolic mechanisms within the Indonesian patient population.
METHODS: This observational analytic study utilized a cross-sectional design, incorporating 105 formalin-fixed paraffin-embedded (FFPE) tissue blocks of prostate adenocarcinoma obtained from referral hospitals in Makassar, Indonesia. Immunohistochemistry was used to find out how much ARG2 was expressed, and digital image analysis (QuPath) was used to get an objective H-Score. According to the International Immuno-Oncology Biomarkers Working Group guidelines, the density of TILs was measured on H&E-stained slides. Statistical analyses encompassed Spearman's rank correlation, the Kruskal-Wallis test, and the Wilcoxon Signed-Rank test for spatial analysis.
RESULT: The study population was predominantly characterized by high-grade tumors, with 45.7% categorized as Grade Group V (Gleason Score 9-10). The digital quantification of ARG2 was validated by manual scoring (r = 0.768, p < 0.001). There was no statistically significant correlation between ARG2 expression and TILs density on a global scale (r = 0.048, p = 0.630). Nonetheless, paired spatial analysis indicated a significant local disparity; tumor regions infiltrated by TILs demonstrated substantially diminished ARG2 expression relative to adjacent non-infiltrated regions (p = 0.009). Moreover, ARG2 expression exhibited a significant inverse correlation with WHO Grade Group (p < 0.001), indicating substantial downregulation in high-grade tumors.
CONCLUSION: The expression of Arginase 2 is significantly reduced in high-grade prostate adenocarcinoma, signifying tumor dedifferentiation. Although ARG2 does not universally forecast immune infiltration, it influences the tumor microenvironment locally, with increased expression correlating with immune exclusion.

Keywords:  Arginase 2; Tumor Microenvironment; digital pathology; prostate adenocarcinoma; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.31557/APJCP.2026.27.7.2713
Curr Oncol. 2026 Jun 24. pii: 379. [Epub ahead of print]33(7):

Real-World Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma: Treatment Delivery, Immune Reconstitution, and Cardiac Monitoring During High-Dose IL-2.

Mohamed A Aboelatta, Jabra Zarka, Nika Tchatchua, Noureldin A Aboelatta, Jeffrey E Johnson, James W Jakub, Justin Desroches, Justine Wilson-Miller, Anthony Tabiim, Deepti Behl, Heather N Montane, Lisa A Kottschade, Anastasios Dimou, Matthew S Block, Elisabeth I Heath, Bently Doonan, Mahesh Seetharam, Julian R Molina, Jonathan E Charnin, Paula Gill, Yi Lin, Binav Baral, Svetomir N Markovic, Arkadiusz Z Dudek.

  Background/Objectives: Tumor-infiltrating lymphocyte (TIL) therapy is an important option for patients with metastatic melanoma progressing after standard systemic therapy, but real-world data on treatment delivery, toxicity monitoring, and immune recovery remain limited. We evaluated clinical outcomes, treatment tolerance, immune reconstitution, and cardiac biomarker dynamics across three Mayo Clinic sites. Methods: We retrospectively analyzed adults with metastatic melanoma who received lymphodepleting chemotherapy followed by TIL infusion and high-dose interleukin-2 (IL-2) between April 2024 and December 2025. Clinical outcomes, treatment delivery, and adverse events were assessed. Longitudinal immune monitoring included CD4 and CD8 T-cell counts, CD4:CD8 ratio, and immunoglobulin G (IgG) at baseline and follow-up. In a prespecified cardiac sub-cohort, high-sensitivity troponin (hs-Tn) was measured during IL-2 administration to evaluate associations with cardiac events and IL-2 interruption. Results: Thirty-six patients underwent TIL infusion. The objective response rate was 50.0%, including complete responses in 13.9%, and the disease control rate was 72.2%. Median progression-free survival was 3.61 months, and median overall survival was 12.94 months. M1d disease was associated with inferior overall survival on univariable analysis (HR 6.55, 95% CI 2.03-21.17; p = 0.002), with attenuation after multivariable adjustment. Receipt of ≥3 IL-2 doses was associated with longer overall survival on univariable analysis (HR 0.20, 95% CI 0.06-0.64; p = 0.007), but this association also attenuated after adjustment. Longitudinal immune monitoring demonstrated persistent CD4 lymphopenia through 6 months, sustained inversion of the CD4:CD8 ratio, and declining IgG at months 3 and 6. In the cardiac sub-cohort (24 patients; 87 IL-2 doses), post-dose hs-Tn ≥15 ng/L was associated with clinically significant cardiac events (OR 9.6, 95% CI 1.5-60.6; p = 0.016) and IL-2 interruption (OR 3.4, 95% CI 1.1-10.7; p = 0.036). For cardiac events, hs-Tn ≥15 ng/L had 100% sensitivity and 100% negative predictive value. Conclusions: In routine practice, TIL therapy was feasible and active in metastatic melanoma. M1d disease identified a subgroup with poor survival, peri-dose hs-Tn showed promise as a tool to support safer IL-2 delivery, and prolonged CD4 suppression with IgG decline suggests that recovery after TIL therapy extends beyond initial hematologic reconstitution. These findings support prospective validation of biomarker-guided IL-2 monitoring and extended post-treatment immune surveillance.

Keywords:  adoptive cell therapy; cardiac toxicity; immune reconstitution; interleukin-2; metastatic melanoma; real-world outcomes; troponin; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/curroncol33070379
Front Oncol. 2026 ;16 1811658

Histopathological biomarkers of immunotherapy outcome in advanced colorectal cancer: a multicentre retrospective study.

Jianying Chen, Yanzhi Chen, Zhigang Chen.

   Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced colorectal cancer (aCRC), but clinical benefit remains largely confined to patients with deficient mismatch repair (dMMR). Responses among patients with proficient mismatch repair (pMMR) are heterogeneous, underscoring the need for accessible biomarkers that can refine patient stratification beyond MMR status. Histopathological features on routine hematoxylin and eosin (H&E)-stained slides may reflect the immune and stromal architecture of the tumor microenvironment. This study investigated the prognostic value and treatment-outcome associations of standardized stromal tumor-infiltrating lymphocytes (sTILs), tumor-stroma ratio (TSR), and tumor budding (TB) in patients with aCRC treated with ICIs.
Methods: This retrospective multicentre study included 210 patients with pathologically confirmed aCRC who received PD-1/PD-L1-based immunotherapy between January 2021 and June 2025. H&E-stained sections were independently assessed by two blinded pathologists. The primary endpoint was progression-free survival (PFS), with objective response rate (ORR) and overall survival (OS) as secondary endpoints. Survival outcomes were analyzed using Kaplan-Meier estimates and Cox proportional hazards models. Inter-observer agreement was evaluated using Cohen's kappa.
Results: At a median follow-up of 22.4 months, high sTILs (≥20%) were associated with a significantly higher ORR than low sTILs (47.2% vs. 15.2%, P<0.001). Patients with low stromal content (TSR ≥50%) experienced longer median PFS compared with those with high stromal content (10.8 vs. 5.2 months; HR 0.48, 95% CI 0.35-0.66; P<0.001). Within the pMMR subgroup (n=162), the combination of high sTILs and low TSR identified an immune-active phenotype with an ORR of 38.5% versus 6.1% in patients with neither feature. Multivariable analysis confirmed high sTILs (HR 0.47, 95% CI 0.26-0.84; P = 0.011) and high-grade tumor budding (HR 2.03, 95% CI 1.39-2.96; P<0.001) as independent prognostic factors for PFS, while TSR demonstrated prognostic value in univariate analysis only.
Conclusions: Standardized assessment of routine H&E-stained histopathological features provides clinically relevant prognostic and outcome-stratifying information in ICI-treated patients in aCRC. These cost-effective biomarkers may complement molecular testing, particularly for stratifying pMMR patients in real-world immunotherapy settings.

Keywords:  colorectal neoplasms; immunotherapy; prognosis.; tumor-infiltrating lymphocytes; tumor-stroma ratio

DOI:  https://doi.org/10.3389/fonc.2026.1811658
Int J Mol Sci. 2026 Jul 09. pii: 6150. [Epub ahead of print]27(14):

Association of BRAF Mutation Status with Histopathological Characteristics and Survival Outcomes in Stage II-III Malignant Melanoma.

Vlad Alexandru Gâta, Daniel Corneliu Leucuța, Radu Alexandru Ilieș, Ștefan Țîțu, Ana Maria Mureșan-Bădescu, Delia Nicoară, Ioan Constantin Pop, Alex Victor Orădan, Maximilian Vlad Muntean, Anda Gâta.

  In patients with advanced or metastatic melanoma, BRAF mutation assessment is routinely performed to identify patients who may benefit from BRAF-targeted therapy. This study aimed to assess the role of BRAF mutation status in relation to histopathological characteristics and survival of patients with stage II and III malignant melanoma. A prospective cohort of 108 patients with pT3 malignant melanoma who were treated in a comprehensive cancer center were included in the analysis. All patients were treated according to contemporary melanoma management guidelines between 2016 and 2024, with a minimum follow-up of 12 months extending to 2025. Overall survival (OS) and progression-free survival (PFS) analyses were performed in the study cohort. The study included 108 patients with stage II-III malignant melanoma, with a mean age of 56.73 ± 13.51 years. Superficial spreading melanoma was the most frequent histological subtype, followed by nodular and acral melanoma. Most tumors were classified as Clark level IV, with a median Breslow thickness of 3 mm, and ulceration was present in the majority of cases. Lymph node involvement was observed in over half of the patients, and BRAF mutations were identified in 56.48% of cases (the most common variant was V600E). Brisk tumor-infiltrating lymphocytes were significantly more frequent in BRAF wild-type tumors compared with BRAF-mutant tumors. When assessing associations with survival, BRAF mutation status was not found to be an independent predictor. In the multivariate Cox model, TIL status was associated with improved OS (HR 3.33, 95% CI 1.41-7.88, p = 0.006). In addition, in the multivariate analysis, TIL status was also associated with improved PFS (HR 5.23, 95% CI 2.22-12.3, p < 0.001). BRAF wild-type tumors were significantly more likely to exhibit a brisk infiltrate. BRAF mutation status was not found to be an independent predictor of survival. TIL status remained significantly associated with OS and PFS in multivariable analysis.

Keywords:  BRAF mutation; histopathology; malignant melanoma; prognosis; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.3390/ijms27146150
Cancers (Basel). 2026 Jul 19. pii: 2327. [Epub ahead of print]18(14):

Prognostic Value of Morphological Characteristics and Immune Microenvironment in High-Grade Serous Cancer (HGSC).

Danijel Antonio Grubišić, Branka Petrić Miše, Toni Čeprnja, Vesna Telesmanić Dobrić, Vesna Čapkun, Snježana Tomić.

  Background/Objectives: High-grade serous ovarian carcinoma (HGSC) is the most aggressive subtype of epithelial ovarian cancer and is characterized by marked heterogeneity of the tumor immune microenvironment. SET morphology has been associated with homologous recombination deficiency and BRCA1/2 mutations; however, its relationship with the immune microenvironment and progression-free survival (PFS) remains insufficiently understood. This study investigated the association between SET morphology, immune microenvironment characteristics, and PFS in patients with advanced-stage HGSC. Methods: A retrospective cohort of 305 patients with FIGO stage III-IV HGSC treated with primary surgery between 1996 and 2021 was analyzed. Histopathological assessment included evaluation of SET morphology, stromal and intraepithelial tumor-infiltrating lymphocytes (sTILs and itTILs), tumor immune phenotype, and lymphoid aggregates. Immunohistochemical analyses included CD8 and PD-L1 expression. Associations between SET morphology and immune parameters were evaluated using χ2 and logistic regression analyses. PFS was assessed using Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards regression. Results: SET morphology was significantly associated with higher sTIL and itTIL levels, increased stromal and intraepithelial CD8+ T-cell infiltration, higher PD-L1 TPS and CPS, more frequent primary and secondary lymphoid aggregates, and a predominance of the inflamed immune phenotype (all p < 0.05). Despite these features of an immune-active tumor microenvironment, SET morphology, CD8+ T-cell density, PD-L1 expression, lymphoid aggregates, and immune phenotype were not independently associated with prolonged PFS. In contrast, age remained an independent prognostic factor, with patients older than 55 years having a 50% higher risk of disease progression than younger patients (HR = 1.5, 95% CI: 1.1-2.1; p = 0.012). Higher intraepithelial TIL levels (>10%) were independently associated with improved PFS (HR = 2.1, 95% CI: 1.0-4.4; p = 0.045). Conclusions: SET morphology identifies an immune-active subtype of HGSC characterized by increased immune infiltration and PD-L1 expression but does not independently predict prolonged PFS. The dissociation between immune cell abundance and clinical outcome suggests that immune cell functionality, rather than immune infiltration alone, may determine prognosis. Routine histopathological assessment of SET morphology may facilitate biological characterization of HGSC and provide a practical surrogate marker for future biomarker-driven studies evaluating immunotherapy and targeted treatment strategies.

Keywords:  CD8-positive lymphocytes; PD-L1; SET morphology; high-grade serous ovarian cancer; immunophenotype; lymphoid aggregates; ovarian cancer immunology; progression-free survival; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/cancers18142327
Front Immunol. 2026 ;17 1917753

Correction: HLA-G expression in non-small cell lung cancer: prognostic significance and interplay with PD-L1 and CD8+ tumor-infiltrating lymphocytes.

Giulia Querzoli, Giuseppe Bogina, Marcella Marconi, Nicola Tumino, Paola Vacca, Luisella Righi, Sara Pilotto, Anna Caliò, Luca Cima, Stefano Gobbo, Matthew J Cecchini, Gaetano Paolino, Francesco Ciompi, Roberto S Accolla, Aldo Scarpa, Gianluigi Lunardi, Emanuela Marcenaro, Lorenzo Moretta, Giuseppe Zamboni, Enrico Munari.

  [This corrects the article DOI: 10.3389/fimmu.2026.1732852.].

Keywords:  HLA-G; PD-L1; immune evasion; non-small cell lung cancer; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2026.1917753
Hum Vaccin Immunother. 2026 Dec;22(1): 2708435

The evolution of cellular therapies in sarcoma: Breakthroughs, challenges, and future directions.

Chalothorn Wannaphut, Prapassorn Thirasastr, John Livingston, Dejka Araujo, Anthony Conley, Emily Keung, Christina Roland, Neeta Somaiah.

  Cellular therapies representa promising area of immunotherapy for advanced cancers,therapies including T cell receptor (TCR) therapies, chimeric antigen receptor (CAR) T cell therapies, tumor-infiltrating lymphocyte (TIL) therapies, and natural killer (NK) cell therapies.Sarcomas pose unique challenges due to their molecular complexity and immunosuppressive tumor microenvironment (TME). TCRtherapiesargeting antigens likeNY-ESO-1, MAGE-A4, and PRAME have shown efficacy, highlighted by the FDA's accelerated approval of afamitresgene autoleucel targeting MAGE-A4 for synovial sarcoma.CAR-T cell therapies targeting HER2, GD2, and B7-H3, along with TIL, and NK cell therapies are also under investigation.However, many are in early stages of clinical development, and their effectiveness may vary by sarcoma subtype. Overcoming challenges such as immunosuppressive TME, antigen escape, lack of T-cell persistence, and off-target toxicities is crucial to improving outcomes for sarcoma patients. This review summarizes the evolution of cellular therapies,ongoing research, challenges, and future directions in this field.

Keywords:  CAR-T cell therapy; Cellular therapy; T cell receptor therapy; sarcoma; tumor-infiltrating lymphocyte therapy

DOI:  https://doi.org/10.1080/21645515.2026.2708435
Melanoma Res. 2026 Jul 28.

Spatial T lymphocyte infiltration into the primary melanoma tumor associates with survival.

Sharon N Edmiston, Yi-Hsuan S Tsai, David L Corcoran, Honglin Hao, Eloise A Parrish, Paul B Googe, Ronglai Shen, Pei Fen Kuan, David W Ollila, Kathleen Conway, Nancy E Thomas.

  Tumor infiltrating lymphocyte grade is a prognostic indicator for patients with cutaneous invasive primary melanoma and assigned one of three-levels (brisk, nonbrisk, or absent). We sought to develop objective, quantitative measures of T lymphocyte subtypes spatially within the tumor microenvironment. We applied multiplex whole-slide immunohistochemistry/immunofluorescence to 80 melanomas, using S100 to identify tumor cells (S100+) and CD3 and CD8 to identify noncytotoxic T lymphocytes (CD3+CD8-), cytotoxic CD8+ T lymphocytes (CD3+CD8+), and total T lymphocytes (CD3+CD8- plus CD3+CD8+). We used image analysis to spatially locate the T lymphocyte subtypes within the whole tumor, the tumor center (175 µm into the tumor), and the tumor margin (within 100 µm outside the tumor). T lymphocyte subtypes were quantified for density as CD3+CD8- and CD3+CD8+ cells colocalized with intact nuclei/µm2. Melanoma-specific survival, adjusted for American Joint Committee on Cancer eighth edition stage, improved when a higher density of each T lymphocyte subtype (CD3+CD8-; CD3+CD8+) infiltrated 175 µm into the tumor center or total T lymphocytes infiltrated into the whole tumor (hazard ratios: 0.72-0.77; all P < 0.05). Improved melanoma-specific survival is significantly associated with high density of CD3+CD8- T lymphocytes in the margin after stage adjustment. Our results indicate spatial location of T lymphocyte subset infiltration within the tumor microenvironment is important for predicting melanoma-specific survival.

Keywords:  melanoma; pathology; skin cancer; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1097/CMR.0000000000001127