bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒11‒26
37 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Targeting Myeloid-Derived Suppressor Cell Trafficking as a Novel Immunotherapeutic Approach in Microsatellite Stable Colorectal Cancer.
  2. Interleukin 35: New Target for Immunotherapy Targeting the Tumor Microenvironment.
  3. Exosome derived from tumor-associated macrophages: biogenesis, functions, and therapeutic implications in human cancers.
  4. Advances in Polymeric Micelles: Responsive and Targeting Approaches for Cancer Immunotherapy in the Tumor Microenvironment.
  5. MiR-506 Promotes Antitumor Immune Response in Pancreatic Cancer by Reprogramming Tumor-Associated Macrophages toward an M1 Phenotype.
  6. Cancer-Associated Fibroblasts in Gastrointestinal Cancers: Unveiling Their Dynamic Roles in the Tumor Microenvironment.
  7. A metabolic axis of immune intractability.
  8. Tumor macrophage functional heterogeneity can inform the development of novel cancer therapies.
  9. Understanding immune checkpoints and PD-1/PD-L1-mediated immune resistance towards tumour immunotherapy.
  10. Metastasis suppressor genes and their role in the tumor microenvironment.
  11. Ginsenoside Rh2 augmented anti-PD-L1 immunotherapy by reinvigorating CD8+ T cells via increasing intratumoral CXCL10.
  12. Immunotherapeutic Agents for Intratumoral Immunotherapy.
  13. Hypoxia-regulated exosomes mediate M2 macrophage polarization and promote metastasis in chondrosarcoma.
  14. The cellular trajectories of tumor-associated macrophages decipher the heterogeneity of pancreatic cancer.
  15. CX3CR1-Expressing Immune Cells Infiltrate the Tumor Microenvironment and Promote Radiation Resistance in a Mouse Model of Lung Cancer.
  16. Immunotherapy for colorectal cancer: Rational strategies and novel therapeutic progress.
  17. Curcumin Disrupts a Positive Feedback Loop between ADMSCs and Cancer Cells in the Breast Tumor Microenvironment via the CXCL12/CXCR4 Axis.
  18. Role of Microenvironmental Components in Head and Neck Squamous Cell Carcinoma.
  19. Emerging Role of Circular RNAs in Hepatocellular Carcinoma Immunotherapy.
  20. A Vaccine against Cancer: Can There Be a Possible Strategy to Face the Challenge? Possible Targets and Paradoxical Effects.
  21. Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity.
  22. The Role of the Tumor Microenvironment in Triple-Positive Breast Cancer Progression and Therapeutic Resistance.
  23. Interleukin-1 receptor accessory protein (IL-1RAP): A magic bullet candidate for immunotherapy of human malignancies.
  24. Stromal-Modulated Epithelial-to-Mesenchymal Transition in Cancer Cells.
  25. RGS5 maintaining vascular homeostasis is altered by the tumor microenvironment.
  26. Harnessing the Electrochemical Effects of Electroporation-Based Therapies to Enhance Anti-tumor Immune Responses.
  27. Improving the therapeutic efficacy of oncolytic viruses for cancer: targeting macrophages.
  28. Colorectal Liver Metastasis: Can Cytokines Make the Difference?
  29. Identification of Surface Markers and Functional Characterization of Myeloid Derived Suppressor Cell-Like Adherent Cells.
  30. Intracellular Major Histocompatibility Complex Class II and C-X-C Motif Chemokine Ligand 10-Expressing Neutrophils Indicate the State of Anti-Tumor Activity Induced by Bacillus Calmette-Guérin.
  31. Vitamin B5 Supports Oncogenic Metabolism in MYC-Driven Breast Cancer.
  32. Loss of B1 and marginal zone B cells during ovarian cancer.
  33. The role of host response to chemotherapy: resistance, metastasis and clinical implications.
  34. Neuroblastoma: an ongoing cold front for cancer immunotherapy.
  35. Novel immune checkpoint targets: A promising therapy for cancer treatments.
  36. Cell fusion upregulates PD-L1 expression for evasion from immunosurveillance.
  37. The paths and challenges of "off-the-shelf" CAR-T cell therapy: An overview of clinical trials.
  1. Cancers (Basel). 2023 Nov 20. pii: 5484. [Epub ahead of print]15(22):
    Targeting Myeloid-Derived Suppressor Cell Trafficking as a Novel Immunotherapeutic Approach in Microsatellite Stable Colorectal Cancer.
    Benny Johnson.
      Myeloid-derived suppressor cells (MDSCs) are a unique subset of immune cells that promote an immunosuppressive phenotype due to their impacts on CD8 and regulatory T cell function. The inhibition of MDSC trafficking to the tumor microenvironment (TME) may represent a novel target in microsatellite stable (MSS) colorectal cancer with the potential to reprogram the immune system. Here, we review the rationale of inhibiting myeloid suppressor cell trafficking in treatment-refractory MSS colorectal cancer and circulating tumor DNA (ctDNA) positive settings to determine whether this approach can serve as a backbone for promoting immunotherapy response in this difficult-to-treat disease.
    Keywords:  immunotherapy; microsatellite stable colorectal cancer; minimal residual disease; myeloid-derived suppressor cells; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15225484
  2. Mol Cancer Ther. 2023 Nov 18.
    Interleukin 35: New Target for Immunotherapy Targeting the Tumor Microenvironment.
    Pengcheng Yi, Wenjun Yu, Yanhong Xiong, Yao Dong, Qiang Huang, Yue Lin, Yunfei Du, Fuzhou Hua.
      Interleukin 35 (IL-35) is a newly discovered inhibitory cytokine of the interleukin 12 family. More recently, IL-35 was found to be increased in the tumor microenvironment (TME) and peripheral blood of many cancer patients, indicating that it plays an important role in TME. Tumors secrete cytokines that recruit myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg) into the TME to promote malignant progression which is a great challenge for cancer treatment. Radiotherapy causes serious adverse effects, and tumor resistance to immune checkpoint inhibitors is still an unsolved challenge.New cancer therapy approaches are urgently needed. Numerous studies have shown that IL-35 can recruit immunosuppressive cells to enable tumor immune escape by promoting the conversion of immune cells into a tumor growth-promoting phenotype as well as facilitating tumor angiogenesis. IL-35-neutralizing antibodies were found to boost the chemotherapeutic effect of gemcitabine and considerably reduce the microvascular density. Therefore, targeting IL-35 in the TME provides a promising cancer treatment target. In addition, IL-35 may be used as an independent prognostic factor for some tumors in the near future. This review intends to reveal the interplay of IL-35 with immune cells in the tumor microenvironment, which may provide new options for cancer treatment.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-23-0242
  3. Biomark Res. 2023 Nov 19. 11(1): 100
    Exosome derived from tumor-associated macrophages: biogenesis, functions, and therapeutic implications in human cancers.
    Manli Zhou, Xiaoyun He, Cheng Mei, Chunlin Ou.
      Tumor-associated macrophages (TAMs), one of the most abundant immune cell types in the tumor microenvironment (TME), account for approximately 50% of the local hematopoietic cells. TAMs play an important role in tumorigenesis and tumor development through crosstalk between various immune cells and cytokines in the TME. Exosomes are small extracellular vesicles with a diameter of 50-150 nm, that can transfer biological information (e.g., proteins, nucleic acids, and lipids) from secretory cells to recipient cells through the circulatory system, thereby influencing the progression of various human diseases, including cancer. Recent studies have suggested that TAMs-derived exosomes play crucial roles in malignant cell proliferation, invasion, metastasis, angiogenesis, immune responses, drug resistance, and tumor metabolic reprogramming. TAMs-derived exosomes have the potential to be targeted for tumor therapy. In addition, the abnormal expression of non-coding RNAs and proteins in TAMs-derived exosomes is closely related to the clinicopathological features of patients with cancer, and these exosomes are expected to become new liquid biopsy markers for the early diagnosis, prognosis, and monitoring of tumors. In this review, we explored the role of TAMs-derived exosomes in tumorigenesis to provide new diagnostic biomarkers and therapeutic targets for cancer prevention.
    Keywords:  Exosomes; Liquid biopsy; Metabolic reprogramming; Therapeutic target; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1186/s40364-023-00538-w
  4. Pharmaceutics. 2023 Nov 13. pii: 2622. [Epub ahead of print]15(11):
    Advances in Polymeric Micelles: Responsive and Targeting Approaches for Cancer Immunotherapy in the Tumor Microenvironment.
    Lichun Cheng, Jiankun Yu, Tangna Hao, Wenshuo Wang, Minjie Wei, Guiru Li.
      In recent years, to treat a diverse array of cancer forms, considerable advancements have been achieved in the field of cancer immunotherapies. However, these therapies encounter multiple challenges in clinical practice, such as high immune-mediated toxicity, insufficient accumulation in cancer tissues, and undesired off-target reactions. To tackle these limitations and enhance bioavailability, polymer micelles present potential solutions by enabling precise drug delivery to the target site, thus amplifying the effectiveness of immunotherapy. This review article offers an extensive survey of recent progress in cancer immunotherapy strategies utilizing micelles. These strategies include responsive and remodeling approaches to the tumor microenvironment (TME), modulation of immunosuppressive cells within the TME, enhancement of immune checkpoint inhibitors, utilization of cancer vaccine platforms, modulation of antigen presentation, manipulation of engineered T cells, and targeting other components of the TME. Subsequently, we delve into the present state and constraints linked to the clinical utilization of polymeric micelles. Collectively, polymer micelles demonstrate excellent prospects in tumor immunotherapy by effectively addressing the challenges associated with conventional cancer immunotherapies.
    Keywords:  cancer immunotherapy; polymeric micelles; responsive delivery systems; targeted drug delivery; tumor microenvironment
    DOI:  https://doi.org/10.3390/pharmaceutics15112622
  5. Biomedicines. 2023 Oct 24. pii: 2874. [Epub ahead of print]11(11):
    MiR-506 Promotes Antitumor Immune Response in Pancreatic Cancer by Reprogramming Tumor-Associated Macrophages toward an M1 Phenotype.
    Tiantian Yang, Yitong Han, Junhang Chen, Xiaoyu Liang, Longhao Sun.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer with a poor prognosis, and effective treatments for PDAC are lacking. In this study, we hypothesized that miR-506 promotes antitumor immune response in PDAC by reprogramming tumor-associated macrophages toward an M1 phenotype to reverse its immunosuppressive tumor microenvironment (TME). First, the relationship between TME and the expression of miR-506 was assessed using clinical samples. Our results provided evidence that lower expression of miR-506 was associated with poor prognosis and immunosuppressive TME in PDAC patients. In addition, miR-506 inhibit the PDAC progression and reversed its immunosuppressive microenvironment in a macrophage-dependent manner. Next, we established a PDAC mouse model by orthotopic injection to further explore the role of miR-506 in vivo. Mechanistic investigations demonstrated that miR-506 could reprogram the polarization of M2-like macrophages toward an M1-like phenotype through targeting STAT3. Meanwhile, miR-506 could also sensitize PDAC to anti-PD-1 immunotherapy, because the tumor microenvironment remodeling effects of miR-506 could reprogram macrophage polarization and subsequently promote cytotoxic T lymphocyte (CTL) infiltration. These findings suggest a relationship between miR-506 and TME, especially M2-like macrophages, thus providing novel insights into mechanisms of tumor progression and potential immunotherapeutic targets for further clinical treatment.
    Keywords:  miR-506; pancreatic cancer; reprogram; signal transducer and activator of transcription 3; tumor-associated macrophage
    DOI:  https://doi.org/10.3390/biomedicines11112874
  6. Int J Mol Sci. 2023 Nov 19. pii: 16505. [Epub ahead of print]24(22):
    Cancer-Associated Fibroblasts in Gastrointestinal Cancers: Unveiling Their Dynamic Roles in the Tumor Microenvironment.
    Noor N Al-Bzour, Ayah N Al-Bzour, Obada E Ababneh, Moayad M Al-Jezawi, Azhar Saeed, Anwaar Saeed.
      Gastrointestinal cancers are highly aggressive malignancies with significant mortality rates. Recent research emphasizes the critical role of the tumor microenvironment (TME) in these cancers, which includes cancer-associated fibroblasts (CAFs), a key component of the TME that have diverse origins, including fibroblasts, mesenchymal stem cells, and endothelial cells. Several markers, such as α-SMA and FAP, have been identified to label CAFs, and some specific markers may serve as potential therapeutic targets. In this review article, we summarize the literature on the multifaceted role of CAFs in tumor progression, including their effects on angiogenesis, immune suppression, invasion, and metastasis. In addition, we highlight the use of single-cell transcriptomics to understand CAF heterogeneity and their interactions within the TME. Moreover, we discuss the dynamic interplay between CAFs and the immune system, which contributes to immunosuppression in the TME, and the potential for CAF-targeted therapies and combination approaches with immunotherapy to improve cancer treatment outcomes.
    Keywords:  cancer-associated fibroblasts; gastrointestinal malignancies; immune system; single-cell analysis
    DOI:  https://doi.org/10.3390/ijms242216505
  7. Cancer Immunol Res. 2023 Nov 21.
    A metabolic axis of immune intractability.
    Dominique C Hinshaw, Meet Patel, Lalita A Shevde.
      Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are re-enacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0433
  8. Trends Immunol. 2023 Dec;pii: S1471-4906(23)00214-4. [Epub ahead of print]44(12): 971-985
    Tumor macrophage functional heterogeneity can inform the development of novel cancer therapies.
    Ibraheem Nasir, Conor McGuinness, Ashleigh R Poh, Matthias Ernst, Phillip K Darcy, Kara L Britt.
      Macrophages represent a key component of the tumor microenvironment (TME) and are largely associated with poor prognosis. Therapeutic targeting of macrophages has historically focused on inhibiting their recruitment or reprogramming their phenotype from a protumor (M2-like) to an antitumor (M1-like) one. Unfortunately, this approach has not provided clinical breakthroughs that have changed practice. Emerging studies utilizing single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics have improved our understanding of the ontogeny, phenotype, and functional plasticity of macrophages. Overlaying the wealth of current information regarding macrophage molecular subtypes and functions has also identified novel therapeutic vulnerabilities that might drive better control of tumor-associated macrophages (TAMs). Here, we discuss the functional profiling of macrophages and provide an update of novel macrophage-targeted therapies in development.
    Keywords:  TAM function; macrophage polarization; macrophage-targeted therapy; tumour-associated macrophages
    DOI:  https://doi.org/10.1016/j.it.2023.10.007
  9. 3 Biotech. 2023 Dec;13(12): 411
    Understanding immune checkpoints and PD-1/PD-L1-mediated immune resistance towards tumour immunotherapy.
    Sidhartha Singh, Navneet Singh, Manoj Baranwal, Siddharth Sharma, S S Kirthiga Devi, Sandeep Kumar.
      Immunotherapy has emerged as a transformative approach in the treatment of various cancers, offering new hope for patients previously faced with limited treatment options. A cornerstone of cancer immunotherapy lies in targeting immune checkpoints, particularly the programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway. Immune checkpoints serve as crucial regulators of the immune response, preventing excessive immune activity and maintaining self-tolerance. PD-1, expressed on the surface of T cells, and its ligand PD-L1, expressed on various cell types, including cancer cells and immune cells, play a central role in this regulatory process. Although the success rate associated with these immunotherapies is very promising, most patients still show intrinsic or acquired resistance. Since the mechanisms related to PD-1/PD-L1 resistance are not well understood, an in-depth analysis is necessary to improve the success rate of anti-PD-1/PD-L1 therapy. Hence, here we provide an overview of PD-1, its ligand PD-L1, and the resistance mechanism towards PD-1/PD-L1. Furthermore, we have discussed the plausible solution to increase efficacy and clinical response. For the following research, joint endeavours of clinicians and basic scientists are essential to address the limitation of resistance towards immunotherapy.
    Keywords:  Anti-tumour activity; Immune checkpoint pathways; PD-1 blockade; T cell reactivity
    DOI:  https://doi.org/10.1007/s13205-023-03826-2
  10. Cancer Metastasis Rev. 2023 Nov 20.
    Metastasis suppressor genes and their role in the tumor microenvironment.
    Cristina Megino-Luque, Jose Javier Bravo-Cordero.
      The metastatic cascade is a complex process with multiple factors contributing to the seeding and growth of cancer cells at metastatic sites. Within this complex process, several genes have been identified as metastasis suppressors, playing a role in the inhibition of metastasis. Interestingly, some of these genes have been shown to also play a role in regulating the tumor microenvironment. In this review, we comment on the recent developments in the biology of metastasis suppressor genes and their crosstalk with the microenvironment.
    Keywords:  Cancer; Metastasis; Metastasis suppresor genes; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10555-023-10155-6
  11. Pharmacol Res. 2023 Nov 19. pii: S1043-6618(23)00344-4. [Epub ahead of print]198 106988
    Ginsenoside Rh2 augmented anti-PD-L1 immunotherapy by reinvigorating CD8+ T cells via increasing intratumoral CXCL10.
    Mu-Yang Huang, Yu-Chi Chen, Wen-Yu Lyu, Xin-Yu He, Zi-Han Ye, Can-Yu Huang, Xin-Ling He, Xiuping Chen, Xiaobing Chen, Baoxian Zhang, Guoyin Kai, Xiaolei Zhang, Ting Li, Mingqing Huang, Jin-Jian Lu.
      Profiting from the sustained clinical improvement and prolonged patient survival, immune checkpoint blockade of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has emerged as a revolutionary cancer therapy approach. However, the anti-PD-1/PD-L1 antibodies only achieve a clinical response rate of approximately 20%. Herein, we identified a novel combination strategy that Chinese medicine ginseng-derived ginsenoside Rh2 (Rh2) markedly improved the anti-cancer efficacy of anti-PD-L1 antibody in mice bearing MC38 tumor. Rh2 combined with anti-PD-L1 antibody (combo treatment) further triggered the infiltration, proliferation and activation of CD8+ T cells in the tumor microenvironment (TME). Depletion of CD8+ T cells by mouse CD8 blocking antibody abolished the anti-cancer effect of combo treatment totally. Mechanistically, combo treatment further increased the expression of CXCL10 through activating TBK1-IRF3 signaling pathway, explaining the increased infiltration of T cells. Employing anti- CXC chemokine receptor 3 (CXCR3) blocking antibody prevented the T cells infiltration and abolished the anti-cancer effect of combo treatment. Meanwhile, combo treatment increased the percentage of M1-like macrophages and raised the ratio of M1/M2 macrophages in TME. By comparing the anti-cancer effect of combo treatment among MC38, CT26 and 4T1 tumors, resident T cells were considered as a prerequisite for the effectiveness of combo treatment. These findings demonstrated that Rh2 potentiated the anti-cancer effect of PD-L1 blockade via promoting the T cells infiltration and activation, which shed a new light on the combination strategy to enhance anti-PD-L1 immunotherapy by using natural product Rh2.
    Keywords:  Combination treatment; Ginsenoside Rh2; PD-1/PD-L1; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.phrs.2023.106988
  12. Vaccines (Basel). 2023 Nov 14. pii: 1717. [Epub ahead of print]11(11):
    Immunotherapeutic Agents for Intratumoral Immunotherapy.
    Chih-Rong Shyr, Lang-Chi Liu, Hui-Shan Chien, Chi-Ping Huang.
      Immunotherapy using systemic immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cells has revolutionized cancer treatment, but it only benefits a subset of patients. Systemic immunotherapies cause severe autoimmune toxicities and cytokine storms. Immune-related adverse events (irAEs) plus the immunosuppressive tumor microenvironment (TME) have been linked to the inefficacy of systemic immunotherapy. Intratumoral immunotherapy that increases immunotherapeutic agent bioavailability inside tumors could enhance the efficacy of immunotherapies and reduce systemic toxicities. In preclinical and clinical studies, intratumoral administration of immunostimulatory agents from small molecules to xenogeneic cells has demonstrated antitumor effects not only on the injected tumors but also against noninjected lesions. Herein, we review and discuss the results of these approaches in preclinical models and clinical trials to build the landscape of intratumoral immunotherapeutic agents and we describe how they stimulate the body's immune system to trigger antitumor immunity as well as the challenges in clinical practice. Systemic and intratumoral combination immunotherapy would make the best use of the body's immune system to treat cancers. Combining precision medicine and immunotherapy in cancer treatment would treat both the mutated targets in tumors and the weakened body's immune system simultaneously, exerting maximum effects of the medical intervention.
    Keywords:  antitumor immunity; body; immunotherapeutic; intratumoral; neoantigen; xenoantigen
    DOI:  https://doi.org/10.3390/vaccines11111717
  13. Aging (Albany NY). 2023 Nov 21. 15
    Hypoxia-regulated exosomes mediate M2 macrophage polarization and promote metastasis in chondrosarcoma.
    Sheng-Mou Hou, Chih-Yang Lin, Yi-Chin Fong, Chih-Hsin Tang.
      Chondrosarcoma is a primary malignant bone tumor. Traditional therapy is not very effective, and it is prone to metastasis in the late stage. The tumor microenvironment (TME) plays a key role in the progression and metastasis of chondrosarcoma, and hypoxia is one of the key factors in the formation of TME. However, the detailed mechanism of how hypoxia affects tumor progression and metastasis in chondrosarcoma is still not fully understood. In this study, we focused on the mechanism of interaction between hypoxic chondrosarcoma cells (SW1353) and macrophages. Our results suggest that hypoxia enhances the release of exosomes from chondrosarcoma cells. These hypoxia-induced exosomes promoted macrophage polarization towards the M2 phenotype, characterized by the expression of CD163 and CD206, but not the M1 phenotype, characterized by CD86 expression. Further analysis revealed that M2 macrophages polarized by exosomes expressed arginase-1 and feedback to chondrosarcoma cells to promote migration. These results suggest that chondrosarcoma cells secrete more exosomes in a hypoxic microenvironment, and these hypoxia-derived exosomes induce the polarization of macrophages into an M2 phenotype, ultimately promoting the metastatic behavior of chondrosarcoma cells.
    Keywords:  chondrosarcoma; exosome; macrophage; metastasis
    DOI:  https://doi.org/10.18632/aging.205230
  14. Funct Integr Genomics. 2023 Nov 22. 23(4): 343
    The cellular trajectories of tumor-associated macrophages decipher the heterogeneity of pancreatic cancer.
    Jiajing Lin, Fengchun Lu, Yuwei Wu, Heguang Huang, Yu Pan.
      Emerging evidence indicates that the interactions and dynamic changes among tumor-associated macrophages (TAMs) are pivotal in molding the tumor microenvironment (TME), thereby influencing diverse clinical outcomes. However, the potential clinical ramifications of these evolutionary shifts in tumor-associated macrophages within pancreatic adenocarcinoma (PAAD) remain largely unexamined. Single-cell RNA sequencing (scRNA-seq) data were retrieved from the Tumor Immune Single-cell Hub. The Seurat and Monocle algorithms were employed to elucidate the progression of TAMs, using non-negative matrix factorization (NMF) to determine molecular classifications. Subsequently, the prognosis, biological characteristics, genomic modifications, and immune landscape across various clusters were interpreted. Furthermore, the sensitivity of potential therapeutic drugs between subtypes was predicted. Cellular experiments were conducted to explore the function of the NR1H3 gene in pancreatic cancer. These experiments encompassed gene knockdown, proliferation assessment, clone formation evaluation, transwell examination, and apoptosis analysis. Trajectory gene expression analysis of tumor-associated macrophages identified three disparate clusters, each associated with different clinical outcomes Compared to clusters C1 and C2, cluster C3 is seemingly at a less advanced pathological stage and associates with a relatively favorable prognosis. Further investigation revealed pronounced genetic instability in cluster C2, whereas cluster C3 demonstrated notable genetic stability. Cluster C1, characterized as "immune-hot," exhibits an abundance of immune cells and elevated immune checkpoint expression, suggesting its suitability for immunotherapy. Furthermore, several potential therapeutic agents have been pinpointed, potentially facilitating the clinical application of these insights. Cell assays indicated that NR1H3 knockdown markedly induced apoptosis and suppressed clonogenesis, migration, and proliferation of pancreatic cancer cells in the PTAU-8988 and PANC-1 cell lines. Overall, our study discerned three clusters with unique characteristics, defined by the evolution of TAMs. We propose customized therapeutic strategies for patients within these specific clusters to improve clinical outcomes and optimize clinical management.
    Keywords:  Heterogeneity; Immunotherapy; Pancreatic cancer; Prognosis; Single-cell RNA-seq
    DOI:  https://doi.org/10.1007/s10142-023-01266-y
  15. Cancers (Basel). 2023 Nov 19. pii: 5472. [Epub ahead of print]15(22):
    CX3CR1-Expressing Immune Cells Infiltrate the Tumor Microenvironment and Promote Radiation Resistance in a Mouse Model of Lung Cancer.
    Tamar Ben-Mordechai, Yaacov R Lawrence, Zvi Symon, Ariel Shimoni-Sebag, Uri Amit.
      INTRODUCTION: Chemokine (C-X3-C Motif) Receptor 1 (CX3CR1) is present in a subset of the immune cells in the tumor microenvironment (TME) and plays an essential and diverse role in cancer progression. However, its potential function in the irradiated TME remains unknown.MATERIALS AND METHODS: A mouse lung cancer model was performed by subcutaneously inoculating Lewis Lung Carcinoma (LLC) cells expressing luciferase (Luc-2) and mCherry cells in CX3CR1GFP/GFP, CX3CR1DTR/+, and wild-type (WT) mice. Bioluminescence imaging, clonogenic assay, and flow cytometry were used to assess tumor progression, proliferation, and cell composition after radiation.
    RESULTS: Radiation provoked a significant influx of CX3CR1-expressing immune cells, notably monocytes and macrophages, into the TME. Co-culturing irradiated LLC cells with CX3CR1-deficient monocytes, and macrophages resulted in reduced clonogenic survival and increased apoptosis of the cancer cells. Interestingly, deficiency of CX3CR1 in macrophages led to a redistribution of the irradiated LLC cells in the S-phase, parallel to increased expression of cyclin E1, required for cell cycle G1/S transition. In addition, the deficiency of CX3CR1 expression in macrophages altered the cytokine secretion with a decrease in interleukin 6, a crucial mediator of cancer cell survival and proliferation. Next, LLC cells were injected subcutaneously into CX3CR1DTR/+ mice, sensitive to diphtheria toxin (DT), and WT mice. After injection, tumors were irradiated with 8 Gy, and mice were treated with DT, leading to conditional ablation of CX3CR1-expressing cells. After three weeks, CX3CR1-depleted mice displayed reduced tumor progression. Furthermore, combining the S-phase-specific chemotherapeutic gemcitabine with CX3CR1 cell ablation resulted in additional attenuation of tumor progression.
    CONCLUSIONS: CX3CR1-expressing mononuclear cells invade the TME after radiation therapy in a mouse lung cancer model. CX3CR1 cell depletion attenuates tumor progression following radiation and sensitizes the tumor to S-phase-specific chemotherapy. Thus, we propose a novel strategy to improve radiation sensitivity by targeting the CX3CR1-expressing immune cells.
    Keywords:  cytokines; immunotherapy; lung cancer; radiation
    DOI:  https://doi.org/10.3390/cancers15225472
  16. Int Immunopharmacol. 2023 Nov 21. pii: S1567-5769(23)01381-4. [Epub ahead of print]126 111055
    Immunotherapy for colorectal cancer: Rational strategies and novel therapeutic progress.
    Farangis Rastin, Hossein Javid, Mahsa Akbari Oryani, Nastaran Rezagholinejad, Amir-R Afshari, Mehdi Karimi-Shahri.
      There are increasing incidences and mortality rates for colorectal cancer in the world. It is common for chemotherapy and radiation given to patients with colorectal cancer to cause toxicities that limit their effectiveness and cause cancer cells to become resistant to these treatments. Additional targeted treatments are needed to improve patient's quality of life and outcomes. Immunotherapy has rapidly emerged as an incredibly exciting and promising avenue for cancer treatment in recent years. This innovative approach provides novel options for tackling solid tumors, effectively establishing itself as a new cornerstone in cancer treatment. Specifically, in the realm of colorectal cancer (CRC), there is great promise in developing new drugs that target immune checkpoints, offering a hopeful and potentially transformative solution. While immunotherapy of CRC has made significant advances, there are still obstacles and limitations. CRC patients have a poor response to treatment because of the immune-suppressing function of their tumor microenvironment (TME). In addition to blocking inhibitory immune checkpoints, checkpoint-blocking antibodies may also boost immune responses against tumors. The review summarizes recent advances in immune checkpoint inhibitors (ICIs) for CRC, including CTLA-4, PD-1, PD-L1, LAG-3, and TIM-3.
    Keywords:  Colorectal cancer; Immune checkpoint inhibitors; Immunotherapy
    DOI:  https://doi.org/10.1016/j.intimp.2023.111055
  17. Pharmaceutics. 2023 Nov 15. pii: 2627. [Epub ahead of print]15(11):
    Curcumin Disrupts a Positive Feedback Loop between ADMSCs and Cancer Cells in the Breast Tumor Microenvironment via the CXCL12/CXCR4 Axis.
    Bo-Young Jang, Min Kyoung Shin, Dong-Hee Han, Jung-Suk Sung.
      Adipose tissue has a significant impact on breast cancer initiation and progression owing to its substantial proportion in the breast. Adipose-derived mesenchymal stem cells (ADMSCs) are major players in the breast tumor microenvironment (TME) as they interact with cancer cells. The intricate interaction between ADMSCs and cancer cells not only drives the differentiation of ADMSCs into cancer-associated fibroblasts (CAFs) but also the metastasis of cancer cells, which is attributed to the CXCL12/CXCR4 axis. We investigated the effects of curcumin, a flavonoid known for CXCL12/CXCR4 axis inhibition, on breast TME by analyzing whether it can disrupt the ADMSC-cancer positive loop. Using MCF7 breast cancer cell-derived conditioned medium (MCF7-CM), we induced ADMSC transformation and verified that curcumin diminished the phenotypic change, inhibiting CAF marker expression. Additionally, curcumin suppressed the CXCL12/CXCR4 axis and its downstream signaling both in ADMSCs and MCF7 cells. The CM from ADMSCs, whose ADMSC-to-CAF transformation was repressed by the curcumin treatment, inhibited the positive feedback loop between ADMSCs and MCF7 as well as epithelial-mesenchymal transition in MCF7. Our study showed that curcumin is a potent anti-cancer agent that can remodel the breast TME, thereby restricting the ADMSC-cancer positive feedback loop associated with the CXCL12/CXCR4 axis.
    Keywords:  CXCL12/CXCR4 axis; adipose-derived mesenchymal stem cell; breast cancer; cancer-associated fibroblast; curcumin; tumor microenvironment
    DOI:  https://doi.org/10.3390/pharmaceutics15112627
  18. J Pers Med. 2023 Nov 17. pii: 1616. [Epub ahead of print]13(11):
    Role of Microenvironmental Components in Head and Neck Squamous Cell Carcinoma.
    Enar Jumaniyazova, Anastasiya Lokhonina, Dzhuliia Dzhalilova, Anna Kosyreva, Timur Fatkhudinov.
      Head and neck squamous cell cancer (HNSCC) is one of the ten most common malignant neoplasms, characterized by an aggressive course, high recurrence rate, poor response to treatment, and low survival rate. This creates the need for a deeper understanding of the mechanisms of the pathogenesis of this cancer. The tumor microenvironment (TME) of HNSCC consists of stromal and immune cells, blood and lymphatic vessels, and extracellular matrix. It is known that HNSCC is characterized by complex relationships between cancer cells and TME components. TME components and their dynamic interactions with cancer cells enhance tumor adaptation to the environment, which provides the highly aggressive potential of HNSCC and resistance to antitumor therapy. Basic research aimed at studying the role of TME components in HNSCC carcinogenesis may serve as a key to the discovery of both new biomarkers-predictors of prognosis and targets for new antitumor drugs. This review article focuses on the role and interaction with cancer of TME components such as newly formed vessels, cancer-associated fibroblasts, and extracellular matrix.
    Keywords:  HNSCC; cancer-associated fibroblasts; extracellular matrix; head and neck squamous cell carcinoma; hypoxia in the TME; tumor microenvironments; vascular component
    DOI:  https://doi.org/10.3390/jpm13111616
  19. Int J Mol Sci. 2023 Nov 18. pii: 16484. [Epub ahead of print]24(22):
    Emerging Role of Circular RNAs in Hepatocellular Carcinoma Immunotherapy.
    Tasneem Abaza, Mostafa K Abd El-Aziz, Kerolos Ashraf Daniel, Paraskevi Karousi, Maria Papatsirou, Sherif Ashraf Fahmy, Nadia M Hamdy, Christos K Kontos, Rana A Youness.
      Hepatocellular carcinoma (HCC) is a highly fatal malignancy with limited therapeutic options and high recurrence rates. Recently, immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) have emerged as a new paradigm shift in oncology. ICIs, such as programmed cell death protein 1 (PD-1) inhibitors, have provided a new source of hope for patients with advanced HCC. Yet, the eligibility criteria of HCC patients for ICIs are still a missing piece in the puzzle. Circular RNAs (circRNAs) have recently emerged as a new class of non-coding RNAs that play a fundamental role in cancer pathogenesis. Structurally, circRNAs are resistant to exonucleolytic degradation and have a longer half-life than their linear counterparts. Functionally, circRNAs possess the capability to influence various facets of the tumor microenvironment, especially at the HCC tumor-immune synapse. Notably, circRNAs have been observed to control the expression of immune checkpoint molecules within tumor cells, potentially impeding the therapeutic effectiveness of ICIs. Therefore, this renders them potential cancer-immune biomarkers for diagnosis, prognosis, and therapeutic regimen determinants. In this review, the authors shed light on the structure and functional roles of circRNAs and, most importantly, highlight the promising roles of circRNAs in HCC immunomodulation and their potential as promising biomarkers and immunotherapeutic regimen determinants.
    Keywords:  circular RNAs (circRNAs); cytotoxic T lymphocytes; hepatocellular carcinoma (HCC); immunotherapy; natural killer cells; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/ijms242216484
  20. Vaccines (Basel). 2023 Nov 08. pii: 1701. [Epub ahead of print]11(11):
    A Vaccine against Cancer: Can There Be a Possible Strategy to Face the Challenge? Possible Targets and Paradoxical Effects.
    Roberto Zefferino, Massimo Conese.
      Is it possible to have an available vaccine that eradicates cancer? Starting from this question, this article tries to verify the state of the art, proposing a different approach to the issue. The variety of cancers and different and often unknown causes of cancer impede, except in some cited cases, the creation of a classical vaccine directed at the causative agent. The efforts of the scientific community are oriented toward stimulating the immune systems of patients, thereby preventing immune evasion, and heightening chemotherapeutic agents effects against cancer. However, the results are not decisive, because without any warning signs, metastasis often occurs. The purpose of this paper is to elaborate on a vaccine that must be administered to a patient in order to prevent metastasis; metastasis is an event that leads to death, and thus, preventing it could transform cancer into a chronic disease. We underline the fact that the field has not been studied in depth, and that the complexity of metastatic processes should not be underestimated. Then, with the aim of identifying the target of a cancer vaccine, we draw attention to the presence of the paradoxical actions of different mechanisms, pathways, molecules, and immune and non-immune cells characteristic of the tumor microenvironment at the primary site and pre-metastatic niche in order to exclude possible vaccine candidates that have opposite effects/behaviors; after a meticulous evaluation, we propose possible targets to develop a metastasis-targeting vaccine. We conclude that a change in the current concept of a cancer vaccine is needed, and the efforts of the scientific community should be redirected toward a metastasis-targeting vaccine, with the increasing hope of eradicating cancer.
    Keywords:  TGF-β; cancer-associated fibroblasts; epithelial–mesenchymal transition; immune cells; immunotherapy; metastasis; paradoxical results; tumor microenvironment; tumor-associated macrophages; vaccines
    DOI:  https://doi.org/10.3390/vaccines11111701
  21. Biochim Biophys Acta Rev Cancer. 2023 Nov 20. pii: S0304-419X(23)00171-3. [Epub ahead of print] 189022
    Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity.
    Sirui Zhang, Xiaozhen Zhang, Hanshen Yang, Tingbo Liang, Xueli Bai.
      Glucose metabolism is essential for the activation, differentiation and function of T cells and proper glucose metabolism is required to maintain effective T cell immunity. Dysregulation of glucose metabolism is a hallmark of cancer, and the tumour microenvironment (TME2) can create metabolic barriers in T cells that inhibit their anti-tumour immune function. Targeting glucose metabolism is a promising approach to improve the capacity of T cells in the TME. The efficacy of common immunotherapies, such as immune checkpoint inhibitors (ICIs3) and adoptive cell transfer (ACT4), can be limited by T-cell function, and the treatment itself can affect T-cell metabolism. Therefore, understanding the relationship between immunotherapy and T cell glucose metabolism helps to achieve more effective anti-tumour therapy. In this review, we provide an overview of T cell glucose metabolism and how T cell metabolic reprogramming in the TME regulates anti-tumour responses, briefly describe the metabolic patterns of T cells during ICI and ACT therapies, which suggest possible synergistic strategies.
    Keywords:  Adoptive cell transfer therapy; Glucose metabolism; Immune checkpoint; Metabolic reprogramming; T cell; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189022
  22. Cancers (Basel). 2023 Nov 20. pii: 5493. [Epub ahead of print]15(22):
    The Role of the Tumor Microenvironment in Triple-Positive Breast Cancer Progression and Therapeutic Resistance.
    Qian Pu, Haidong Gao.
      Breast cancer (BRCA) is a highly heterogeneous systemic disease. It is ranked first globally in the incidence of new cancer cases and has emerged as the primary cause of cancer-related death among females. Among the distinct subtypes of BRCA, triple-positive breast cancer (TPBC) has been associated with increased metastasis and invasiveness, exhibiting greater resistance to endocrine therapy involving trastuzumab. It is now understood that invasion, metastasis, and treatment resistance associated with BRCA progression are not exclusively due to breast tumor cells but are from the intricate interplay between BRCA and its tumor microenvironment (TME). Accordingly, understanding the pathogenesis and evolution of the TPBC microenvironment demands a comprehensive approach. Moreover, addressing BRCA treatment necessitates a holistic consideration of the TME, bearing significant implications for identifying novel targets for anticancer interventions. This review expounds on the relationship between critical cellular components and factors in the TPBC microenvironment and the inception, advancement, and therapeutic resistance of breast cancer to provide perspectives on the latest research on TPBC.
    Keywords:  occurrence and development; treatment resistance; triple-positive breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15225493
  23. Crit Rev Oncol Hematol. 2023 Nov 20. pii: S1040-8428(23)00288-3. [Epub ahead of print]193 104200
    Interleukin-1 receptor accessory protein (IL-1RAP): A magic bullet candidate for immunotherapy of human malignancies.
    Ali Zarezadeh Mehrabadi, Faezeh Shahba, Hossein Khorramdelazad, Nazanin Aghamohammadi, Milad Karimi, Kowsar Bagherzadeh, Majid Khoshmirsafa, Ramin Massoumi, Reza Falak.
      IL-1, plays a role in some pathological inflammatory conditions. This pro-inflammatory cytokine also has a crucial role in tumorigenesis and immune responses in the tumor microenvironment (TME). IL-1 receptor accessory protein (IL-1RAP), combined with IL-1 receptor-1, provides a functional complex for binding and signaling. In addition to the direct role of IL-1, some studies demonstrated that IL1-RAP has essential roles in the progression, angiogenesis, and metastasis of solid tumors such as gastrointestinal tumors, lung carcinoma, glioma, breast and cervical cancers. This molecule also interacts with FLT-3 and c-Kit tyrosine kinases and is involved in the pathogenesis of hematological malignancies such as acute myeloid lymphoma. Additionally, IL-1RAP interacts with solute carrier family 3 member 2 (SLC3A2) and thereby increasing the resistance to anoikis and metastasis in Ewing sarcoma. This review summarizes the role of IL-1RAP in different types of cancers and discusses its targeting as a novel therapeutic approach for malignancies.
    Keywords:  Cancer immunotherapy; Chronic inflammation; IL-1 receptor accessory protein; Interleukin-1
    DOI:  https://doi.org/10.1016/j.critrevonc.2023.104200
  24. Biomolecules. 2023 Nov 01. pii: 1604. [Epub ahead of print]13(11):
    Stromal-Modulated Epithelial-to-Mesenchymal Transition in Cancer Cells.
    Huda I Atiya, Grace Gorecki, Geyon L Garcia, Leonard G Frisbie, Roja Baruwal, Lan Coffman.
      The ability of cancer cells to detach from the primary site and metastasize is the main cause of cancer- related death among all cancer types. Epithelial-to-mesenchymal transition (EMT) is the first event of the metastatic cascade, resulting in the loss of cell-cell adhesion and the acquisition of motile and stem-like phenotypes. A critical modulator of EMT in cancer cells is the stromal tumor microenvironment (TME), which can promote the acquisition of a mesenchymal phenotype through direct interaction with cancer cells or changes to the broader microenvironment. In this review, we will explore the role of stromal cells in modulating cancer cell EMT, with particular emphasis on the function of mesenchymal stromal/stem cells (MSCs) through the activation of EMT-inducing pathways, extra cellular matrix (ECM) remodeling, immune cell alteration, and metabolic rewiring.
    Keywords:  ECM remodeling; direct and indirect interaction; mesenchymal stem cells; reprograming
    DOI:  https://doi.org/10.3390/biom13111604
  25. Biol Direct. 2023 Nov 20. 18(1): 78
    RGS5 maintaining vascular homeostasis is altered by the tumor microenvironment.
    Peng Kong, Xu Wang, Ya-Kun Gao, Dan-Dan Zhang, Xiao-Fu Huang, Yu Song, Wen-Di Zhang, Rui-Juan Guo, Han Li, Mei Han.
      BACKGROUND: Regulator of G protein signaling 5 (RGS5), as a negative regulator of G protein-coupled receptor (GPCR) signaling, is highly expressed in arterial VSMCs and pericytes, which is involved in VSMC phenotypic heterogeneity and vascular remodeling in tumors. However, its role in normal and tumor vascular remodeling is controversial.METHODS: RGS5 knockout (Rgs5-KO) mice and RGS5 overexpression or knockdown in VSMCs in vivo by adeno-associated virus type 9 (AAV) carrying RGS5 cDNA or small hairpin RNA (shRNA) targeting RGS5 were used to determine the functional significance of RGS5 in vascular inflammation. RGS5 expression in the triple-negative (TNBCs) and non-triple-negative breast cancers (Non-TNBCs) was determined by immunofluorescent and immunohistochemical staining. The effect of breast cancer cell-conditioned media (BC-CM) on the pro-inflammatory phenotype of VSMCs was measured by phagocytic activity assays, adhesion assay and Western blot.
    RESULTS: We identified that knockout and VSMC-specific knockdown of RGS5 exacerbated accumulation and pyroptosis of pro-inflammatory VSMCs, resulting in vascular remodeling, which was negated by VSMC-specific RGS5 overexpression. In contrast, in the context of breast cancer tissues, the role of RGS5 was completely disrupted. RGS5 expression was increased in the triple-negative breast cancer (TNBC) tissues and in the tumor blood vessels, accompanied with an extensive vascular network. VSMCs treated with BC-CM displayed enhanced pro-inflammatory phenotype and higher adherent with macrophages. Furthermore, tumor-derived RGS5 could be transferred into VSMCs.
    CONCLUSIONS: These findings suggest that tumor microenvironment shifts the function of RGS5 from anti-inflammation to pro-inflammation and induces the pro-inflammatory phenotype of VSMCs that is favorable for tumor metastasis.
    Keywords:  Breast cancer; Regulator of G protein signaling 5; Vascular remodeling; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1186/s13062-023-00437-y
  26. Ann Biomed Eng. 2023 Nov 21.
    Harnessing the Electrochemical Effects of Electroporation-Based Therapies to Enhance Anti-tumor Immune Responses.
    Zaid S Salameh, Kenneth N Aycock, Nastaran Alinezhadbalalami, Khan Mohammad Imran, Iain H McKillop, Irving C Allen, Rafael V Davalos.
      This study introduces a new method of targeting acidosis (low pH) within the tumor microenvironment (TME) through the use of cathodic electrochemical reactions (CER). Low pH is oncogenic by supporting immunosuppression. Electrochemical reactions create local pH effects when a current passes through an electrolytic substrate such as biological tissue. Electrolysis has been used with electroporation (destabilization of the lipid bilayer via an applied electric potential) to increase cell death areas. However, the regulated increase of pH through only the cathode electrode has been ignored as a possible method to alleviate TME acidosis, which could provide substantial immunotherapeutic benefits. Here, we show through ex vivo modeling that CERs can intentionally elevate pH to an anti-tumor level and that increased alkalinity promotes activation of naïve macrophages. This study shows the potential of CERs to improve acidity within the TME and that it has the potential to be paired with existing electric field-based cancer therapies or as a stand-alone therapy.
    Keywords:  Ablation; Anti-tumor; Direct current; Electrochemical; Electroporation; Hepatocellular carcinoma; Immunology; Immunosuppressive; Irreversible electroporation; THP-1; Tumor microenvironment; Tumor-associated macrophages; Warburg effect; pH
    DOI:  https://doi.org/10.1007/s10439-023-03403-x
  27. J Transl Med. 2023 Nov 22. 21(1): 842
    Improving the therapeutic efficacy of oncolytic viruses for cancer: targeting macrophages.
    Zhen Shen, Xiyu Liu, Guixiang Fan, Jintong Na, Qiaoqiao Liu, Faquan Lin, Zhikun Zhang, Liping Zhong.
      Oncolytic viruses (OVs) for cancer treatment are in a rapid stage of development, and the direct tumor lysis and activation of a comprehensive host immune response are irreplaceable advantages of cancer immunotherapy. However, excessive antiviral immune responses also restrict the spread of OVs in vivo and the infection of tumor cells. Macrophages are functionally diverse innate immune cells that phagocytose tumor cells and present antigens to activate the immune response, while also limiting the delivery of OVs to tumors. Studies have shown that the functional propensity of macrophages between OVs and tumor cells affects the overall therapeutic effect of oncolytic virotherapy. How to effectively avoid the restrictive effect of macrophages on OVs and reshape the function of tumor-associated macrophages in oncolytic virotherapy is an important challenge we are now facing. Here, we review and summarize the complex dual role of macrophages in oncolytic virotherapy, highlighting how the functional characteristics of macrophage plasticity can be utilized to cooperate with OVs to enhance anti-tumor effects, as well as highlighting the importance of designing and optimizing delivery modalities for OVs in the future.
    Keywords:  Cancer immunotherapy; Innate immunity; Macrophage; Macrophage reprogramming; Oncolytic virus; Virotherapy
    DOI:  https://doi.org/10.1186/s12967-023-04709-z
  28. Cancers (Basel). 2023 Nov 10. pii: 5359. [Epub ahead of print]15(22):
    Colorectal Liver Metastasis: Can Cytokines Make the Difference?
    Costanza Ballarò, Valeria Quaranta, Gianluigi Giannelli.
      Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. Metastasis is the prime driver of CRC-related mortality, and the liver is the organ most frequently involved. Despite the overall success of current treatments, colorectal liver metastasis (CRLM) is associated with poor prognoses and a survival rate of only 14%. Recent studies have highlighted the importance of the tumor microenvironment (TME) and the crosstalk within it in determining the invasion of distant organs by circulating cancer cells. In the TME, cellular communication is mediated via soluble molecules, among which cytokines have recently emerged as key regulators, involved in every aspect of tumor progression and the metastatic cascade. Indeed, in the serum of CRC patients elevated levels of several cytokines are associated with cancer development and progression. The current review evaluates the role of different cytokines during CRLM development. Additionally, considering the increasing amount of data concerning the importance of cytokine complex networks, we outline the potential of combination treatments using targeted cytokines together with other well-established therapies, such as immune checkpoint blockades, chemotherapy, or gene therapy, to improve therapeutic outcomes.
    Keywords:  chemokines; colorectal cancer; cytokines; liver metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15225359
  29. Adv Biol (Weinh). 2023 Nov 20. e2300159
    Identification of Surface Markers and Functional Characterization of Myeloid Derived Suppressor Cell-Like Adherent Cells.
    John Clyde Co Soriano, Shiho Tsutsumi, Daiya Ohara, Keiji Hirota, Gen Kondoh, Tatsuya Niwa, Hideki Taguchi, Tetsuya Kadonosono, Shinae Kizaka-Kondoh.
      Myeloid-derived suppressor cell (MDSC)-like adherent cells (MLACs) are a recently identified CD11b+ F4/80- myeloid cell subset that can infiltrate tumors early in development and promote their growth. Because of these functions, MLACs play an important role in establishing an immunosuppressive tumor microenvironment (TME). However, the lack of MLAC-specific markers has hampered further characterization of this cell type. This study identifies the gene signature of MLACs by analyzing RNA-sequencing (RNA-seq) and public single-cell RNA-seq data, revealing that MLACs are an independent cell population that are distinct from other intratumoral myeloid cells. After combining proteome analysis of membrane proteins with RNA-seq data, H2-Ab1 and CD11c are indicated as marker proteins that can support the isolation of MLAC subsets from CD11b+ F4/80- myeloid cells by fluorescence-activated cell sorting. The CD11b+ F4/80- H2-Ab1+ and CD11b+ F4/80- CD11c+ MLAC subsets represent approximately half of the MLAC population that is isolated based on their adhesion properties and possess gene signatures and functional properties similar to those of the MLAC population. Additionally, membrane proteome analysis suggests that MLACs express highly heterogeneous surface proteins. This study facilitates an integrated understanding of heterogeneous intratumoral myeloid cells, as well as the molecular and cellular details of the development of an immunosuppressive TME.
    Keywords:  cancer microenvironment; cell surface markers; myeloid cells; tumor immunology
    DOI:  https://doi.org/10.1002/adbi.202300159
  30. Biomedicines. 2023 Nov 15. pii: 3062. [Epub ahead of print]11(11):
    Intracellular Major Histocompatibility Complex Class II and C-X-C Motif Chemokine Ligand 10-Expressing Neutrophils Indicate the State of Anti-Tumor Activity Induced by Bacillus Calmette-Guérin.
    Yuji Takeda, Tomoyuki Kato, Saima Sabrina, Sei Naito, Hiromi Ito, Naoto Emi, Yuya Kuboki, Yuki Takai, Hiroki Fukuhara, Masaki Ushijima, Takafumi Narisawa, Mayu Yagi, Hidenori Kanno, Toshihiko Sakurai, Hayato Nishida, Akemi Araki, Yoshitaka Shimotai, Mikako Nagashima, Yusuke Nouchi, Shinichi Saitoh, Hidetoshi Nara, Norihiko Tsuchiya, Hironobu Asao.
      (1) Background: Inflammatory responses induce the formation of both anti-tumor and pro-tumor neutrophils known as myeloid-derived suppressor cells (MDSCs). Intermittent intravesical infusion of Bacillus Calmette-Guérin (BCG) is an established cancer immunotherapy for non-muscle-invasive bladder cancer (NMIBC). However, the types of neutrophils induced via the inflammatory response to both tumor-bearing and BCG remain unclear. (2) Methods: We therefore analyzed neutrophil dynamics in the peripheral blood and urine of patients with NMIBC who received BCG therapy. Further, we analyzed the effects of BCG in a mouse intraperitoneal tumor model. (3) Results: BCG therapy induced the formation of CXCL10 and MHC class II-positive neutrophils in the urine of patients with NMIBC but did not induce MDSC formation. CXCL10- and MHC class II-expressing neutrophils were detected in peritoneal exudate cells formed after BCG administration. Partial neutrophil depletion using an anti-Ly6G antibody suppressed the upregulation of CXCL10 and MHC class II in neutrophils and reversed the anti-tumor activity of BCG in mouse models. (4) Conclusions: These results indicated that intracellular MHC class II- and CXCL10-expressing neutrophils indicate the state of anti-tumor activity induced via BCG. The status of neutrophils in mixed inflammation of immunosuppressive and anti-tumor responses may therefore be useful for evaluating immunological systemic conditions.
    Keywords:  Bacillus Calmette–Guérin (BCG); C-X-C motif chemokine ligand 10 (CXCL10); bladder cancer; major histocompatibility complex (MHC) class II; myeloid-derived suppressor cells (MDSCs); neutrophils
    DOI:  https://doi.org/10.3390/biomedicines11113062
  31. Cancer Discov. 2023 Nov 22. OF1
    Vitamin B5 Supports Oncogenic Metabolism in MYC-Driven Breast Cancer.
      Pantothetic acid is required for metabolic activity that supports MYC-driven breast tumor growth.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-185
  32. Cell Immunol. 2023 Nov 22. pii: S0008-8749(23)00127-2. [Epub ahead of print]395-396 104788
    Loss of B1 and marginal zone B cells during ovarian cancer.
    Jeffrey Maslanka, Gretel Torres, Jennifer Londregan, Naomi Goldman, Daniel Silberman, John Somerville, James E Riggs.
      Recent advances in immunotherapy have not addressed the challenge presented by ovarian cancer. Although the peritoneum is an "accessible" locus for this disease there has been limited characterization of the immunobiology therein. We investigated the ID8-C57BL/6J ovarian cancer model and found marked depletion of B1 cells from the ascites of the peritoneal cavity. There was also selective loss of the B1 and marginal zone B cell subsets from the spleen. Immunity to antigens that activate these subsets validated their loss rather than relocation. A marked influx of myeloid-derived suppressor cells correlated with B cell subset depletion. These observations are discussed in the context of the housekeeping burden placed on innate B cells during ovarian cancer and to foster consideration of B cell biology in therapeutic strategies to address this challenge.
    Keywords:  B1 cells; Marginal Zone B cells; Ovarian Cancer; Peritoneal cavity; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cellimm.2023.104788
  33. Clin Exp Metastasis. 2023 Nov 24.
    The role of host response to chemotherapy: resistance, metastasis and clinical implications.
    Abhilash Deo, Jonathan P Sleeman, Yuval Shaked.
      Chemotherapy remains the primary treatment for most metastatic cancers. However, the response to chemotherapy and targeted agents is often transient, and concurrent development of resistance is the primary impediment to effective cancer therapy. Strategies to overcome resistance to treatment have focused on cancer cell intrinsic factors and the tumor microenvironment (TME). Recent evidence indicates that systemic chemotherapy has a significant impact on the host that either facilitates tumor growth, allowing metastatic spread, or renders treatment ineffective. These host responses include the release of bone marrow-derived cells, activation of stromal cells in the TME, and induction of different molecular effectors. Here, we provide an overview of chemotherapy-induced systemic host responses that support tumor aggressiveness and metastasis, and which contribute to therapy resistance. Studying host responses to chemotherapy provides a solid basis for the development of adjuvant strategies to improve treatment outcomes and delay resistance to chemotherapy. This review discusses the emerging field of host response to cancer therapy, and its preclinical and potential clinical implications, explaining how under certain circumstances, these host effects contribute to metastasis and resistance to chemotherapy.
    Keywords:  Chemoresistance; Host response; Metastasis; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10585-023-10243-5
  34. J Immunother Cancer. 2023 Nov 22. pii: e007798. [Epub ahead of print]11(11):
    Neuroblastoma: an ongoing cold front for cancer immunotherapy.
    Paul T Kennedy, Demetra Zannoupa, Meong Hi Son, Lekh N Dahal, John F Woolley.
      Neuroblastoma is the most frequent extracranial childhood tumour but effective treatment with current immunotherapies is challenging due to its immunosuppressive microenvironment. Efforts to date have focused on using immunotherapy to increase tumour immunogenicity and enhance anticancer immune responses, including anti-GD2 antibodies; immune checkpoint inhibitors; drugs which enhance macrophage and natural killer T (NKT) cell function; modulation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway; and engineering neuroblastoma-targeting chimeric-antigen receptor-T cells. Some of these strategies have strong preclinical foundation and are being tested clinically, although none have demonstrated notable success in treating paediatric neuroblastoma to date. Recently, approaches to overcome heterogeneity of neuroblastoma tumours and treatment resistance are being explored. These include rational combination strategies with the aim of achieving synergy, such as dual targeting of GD2 and tumour-associated macrophages or natural killer cells; GD2 and the B7-H3 immune checkpoint; GD2 and enhancer of zeste-2 methyltransferase inhibitors. Such combination strategies provide opportunities to overcome primary resistance to and maximize the benefits of immunotherapy in neuroblastoma.
    Keywords:  Immunotherapy; Neuroblastoma; Tumor Microenvironment
    DOI:  https://doi.org/10.1136/jitc-2023-007798
  35. Int Immunopharmacol. 2023 Nov 16. pii: S1567-5769(23)01513-8. [Epub ahead of print]126 111186
    Novel immune checkpoint targets: A promising therapy for cancer treatments.
    Mohsina Patwekar, Nouroz Sehar, Faheem Patwekar, Anuradha Medikeri, Shafat Ali, Rana M Aldossri, Muneeb U Rehman.
      The immune system frequently comprises immunological checkpoints. They serve as a barrier to keep the immune system from overreacting and damaging cells that are robust. Immune checkpoint inhibitors (ICIs) are utilized in immunotherapy to prevent the synergy of partner proteins of checkpoint proteins with auxiliary proteins. Moreover, the T cells may target malignant cells since the "off" signal cannot be conveyed. ICIs, which are mostly composed of monoclonal antibodies (mAbs) against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and anti- programmed death-1/programmed ligand 1 (anti-PD-1/PD-L1), might transform the context of cancer therapy. Further, more patients continued to exhibit adaptive resistance, even though several ICIs demonstrated convincing therapeutic benefits in selective tumor types. Immune checkpoint therapy's overall effectiveness is still lacking at this time. A popular area of study involves investigating additional immune checkpoint molecules. Recent research has found a number of fresh immune checkpoint targets, including NKG2A ligands, TIGIT, B7-H6 ligands, Galectin 3, TIM3, and so on. These targets have been focus of the study, and recent investigational approaches have shown encouraging outcomes. In this review article, we covered the development and present level understanding of these recently identified immune checkpoint molecules, its effectiveness and limitations.
    Keywords:  B7-H6 ligand; Galectin 3; HHLA2 protein; NKG2A ligands; TIGIT; TIM3
    DOI:  https://doi.org/10.1016/j.intimp.2023.111186
  36. Cancer Gene Ther. 2023 Nov 21.
    Cell fusion upregulates PD-L1 expression for evasion from immunosurveillance.
    Youichi Tajima, Futoshi Shibasaki, Hisao Masai.
      MSCs (mesenchymal stem cells), responsible for tissue repair, rarely undergo cell fusion with somatic cells. Here, we show that ~5% of bladder cancer cells (UMUC-3) fuses with bone marrow-derived MSC (BM-MSC) in co-culture and maintains high tumorigenicity. In eleven fusion cell clones that have been established, Mb-scale deletions carried by the bladder cancer cells are mostly absent in the fusion cells, but copy number gains contributed by the cancer cells have stayed. Fusion cells exhibit increased populations of mitotic cells with 3-polar spindles, indicative of genomic instability. They grow faster in vitro and exhibit higher colony formation in anchorage-independent growth assay in soft agar than the parent UMUC-3 does. Fusion cells develop tumors, after 4 weeks of time lag, as efficiently as the parent UMUC-3 does in xenograft experiments. 264 genes are identified whose expression is specifically altered in the fusion cells. Many of them are interferon-stimulated genes (ISG), but are activated in a manner independent of interferon. Among them, we show that PD-L1 is induced in fusion cells, and its knockout decreases tumorigenesis in a xenograft model. PD-L1 is induced in a manner independent of STAT1 known to regulate PD-L1 expression, but is regulated by histone modification, and is likely to inhibit phagocytosis by PD1-expressing macrophages, thus protecting cancer cells from immunological attacks. The fusion cells overexpress multiple cytokines including CCL2 that cause tumor progression by converting infiltrating macrophages to tumor-associated-macrophage (TAM). The results present mechanisms of how cell fusion promotes tumorigenesis, revealing a novel link between cell fusion and PD-L1, and underscore the efficacy of cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41417-023-00693-0
  37. Biomed Pharmacother. 2023 Nov 16. pii: S0753-3322(23)01686-4. [Epub ahead of print]169 115888
    The paths and challenges of "off-the-shelf" CAR-T cell therapy: An overview of clinical trials.
    Vahid Moradi, Azadeh Omidkhoda, Naser Ahmadbeigi.
      The advent of chimeric antigen receptor T cells (CAR-T cells) has made a tremendous revolution in the era of cancer immunotherapy, so that since 2017 eight CAR-T cell products have been granted marketing authorization. All of these approved products are generated from autologous sources, but this strategy faces several challenges such as time-consuming and expensive manufacturing process and reduced anti-tumor potency of patients' T cells due to the disease or previous therapies. The use of an allogeneic source can overcome these issues and provide an industrial, scalable, and standardized manufacturing process that reduces costs and provides faster treatment for patients. Nevertheless, for using allogeneic CAR-T cells, we are faced with the challenge of overcoming two formidable impediments: severe life-threatening graft-versus-host-disease (GvHD) caused by allogeneic CAR-T cells, and allorejection of allogeneic CAR-T cells by host immune cells which is called "host versus graft" (HvG). In this study, we reviewed recent registered clinical trials of allogeneic CAR-T cell therapy to analyze different approaches to achieve a safe and efficacious "off-the-shelf" source for chimeric antigen receptor (CAR) based immunotherapy.
    Keywords:  Allogeneic; CAR (chimeric Antigen Receptor); Clinical; GvHD; Off-the-shelf; Trials
    DOI:  https://doi.org/10.1016/j.biopha.2023.115888
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