ArticleCellular and molecular life sciences : CMLS2021
Melanoma-associated fibroblasts impair CD8+ T cell function and modify expression of immune checkpoint regulators via increased arginase activity.
Article in Cellular and molecular life sciences : CMLS, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 62 citations in OpenAlex.
- MITF-Driven melanoma plasticity as a core mechanism of therapy resistance: integrating microenvironmental signaling, mechanotransduction, and metabolic reprogramming.Cell cycle (Georgetown, Tex.) · 2026Review
- Metabolic reprogramming in cancer-associated fibroblasts: orchestrating the tumor immune microenvironment and response to immune checkpoint blockade.Experimental hematology & oncology · 2026Review
- Triple-Negative Breast Cancer: Molecular Subtypes; Immune Escape; Limitations of Current Immunotherapy; and the BTLA/HVEM/CD160 Axis as an Emerging Target.Current issues in molecular biology · 2026Review
- A bittersweet symphony: soluble mediator networks orchestrate melanoma plasticity and therapeutic adaptation.Frontiers in cell and developmental biology · 2026Review
- Serum Arginase-1 is a predictive biomarker for melanoma patients and a surrogate indicator of systemic myeloid cell fitness.Oncoimmunology · 2025Article
- Anti-FAP CAR-NK cells as a novel targeted therapy against cervical cancer and cancer-associated fibroblasts.Oncoimmunology · 2025Article
- Cancer-Associated Fibroblasts: Origin, Classification, Tumorigenicity, and Targeting for Cancer Therapy.MedComm · 2025Review
- Double-sided niche regulation in skin stem cell and cancer: mechanisms and clinical applications.Molecular cancer · 2025Review
- Cancer‑associated fibroblasts: a pivotal regulator of tumor microenvironment in the context of radiotherapy.Cell communication and signaling : CCS · 2025Review
- The tumor immune microenvironment in primary cutaneous melanoma.Archives of dermatological research · 2025Review
- The Role and Treatment Strategies of Ammonia-Related Metabolism in Tumor Microenvironment.Current gene therapy · 2025Review
- The role of transcription factors in the crosstalk between cancer-associated fibroblasts and tumor cells.Journal of advanced research · 2025Review
- Melanoma-associated fibroblasts in tumor-promotion flammation and antitumor immunity: novel mechanisms and potential immunotherapeutic strategies.Human molecular genetics · 2024Review
- BTLA biology in cancer: from bench discoveries to clinical potentials.Biomarker research · 2024Review
- DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression.Oncogene · 2024Article
- Influencing factors and solution strategies of chimeric antigen receptor T-cell therapy (CAR-T) cell immunotherapy.Oncology research · 2024Review
- The combination of single-cell and RNA sequencing analysis decodes the melanoma tumor microenvironment and identifies novel T cell-associated signature genes.Journal of Cancer · 2024Article
- Interactions between cancer-associated fibroblasts and T-cells: functional crosstalk with targeting and biomarker potential.Upsala journal of medical sciences · 2024Review
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
This study shows that melanoma-associated fibroblasts (MAFs) suppress cytotoxic T lymphocyte (CTL) activity and reveals a pivotal role played by arginase in this phenomenon. MAFs and normal dermal fibroblasts (DFs) were isolated from surgically resected melanomas and identified as Melan-A-/gp100-/FAP+ cells. CTLs of healthy blood donors were activated in the presence of MAF- and DF-conditioned media (CM). Markers of successful CTL activation, cytotoxic degranulation, killing activity and immune checkpoint regulation were evaluated by flow cytometry, ELISPOT, and redirected killing assays. Soluble mediators responsible for MAF-mediated effects were identified by ELISA, flow cytometry, inhibitor assays, and knock-in experiments. In the presence of MAF-CM, activated/non-naïve CTLs displayed dysregulated ERK1/2 and NF-κB signaling, impeded CD69 and granzyme B production, impaired killing activity, and upregulated expression of the negative immune checkpoint receptors TIGIT and BTLA. Compared to DFs, MAFs displayed increased amounts of VISTA and HVEM, a known ligand of BTLA on T cells, increased L-arginase activity and CXCL12 release. Transgenic arginase over-expression further increased, while selective arginase inhibition neutralized MAF-induced TIGIT and BTLA expression on CTLs. Our data indicate that MAF interfere with intracellular CTL signaling via soluble mediators leading to CTL anergy and modify immune checkpoint receptor availability via L-arginine depletion.
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Registered trials
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