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Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Targeting Melanoma-Associated Fibroblasts (MAFs) with Activated γδ (Vδ2) T Cells: An In Vitro Cytotoxicity Model
Anna Hajdara1,2, Uğur Çakır1, Barbara Érsek3
1Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, 1085 Budapest, Hungary.
Abstract:
The tumor microenvironment (TME) has gained considerable scientific attention by playing a role in immunosuppression and tumorigenesis. Besides tumor cells, TME is composed of various other cell types, including cancer-associated fibroblasts (CAFs or MAFs when referring to melanoma-derived CAFs) and tumor-infiltrating lymphocytes (TILs), a subpopulation of which is labeled as γδ T cells. Since the current anti-cancer therapies using γδ T cells in various cancers have exhibited mixed treatment responses, to better understand the γδ T cell biology in melanoma, our research group aimed to investigate whether activated γδ T cells are capable of killing MAFs. To answer this question, we set up an in vitro platform using freshly isolated Vδ2-type γδ T cells and cultured MAFs that were biobanked from our melanoma patients. This study proved that the addition of zoledronic acid (1-2.5 µM) to the γδ T cells was necessary to drive MAFs into apoptosis. The MAF cytotoxicity of γδ T cells was further enhanced by using the stimulatory clone 20.1 of anti-BTN3A1 antibody but was reduced when anti-TCR γδ or anti-BTN2A1 antibodies were used. Since the administration of zoledronic acid is safe and tolerable in humans, our results provide further data for future clinical studies on the treatment of melanoma.
Insights
Activated γδ T cells can kill melanoma-associated fibroblasts (MAFs) with zoledronic acid, enhancing anti-cancer therapy potential. This study investigated γδ T cell and MAF interactions in melanoma.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- The tumor microenvironment (TME) influences cancer progression and immune evasion.
- Cancer-associated fibroblasts (CAFs), or MAFs in melanoma, are key TME components.
- γδ T cells are lymphocytes with potential in cancer immunotherapy, but responses vary.
Purpose of the Study:
- To investigate the cytotoxic potential of activated γδ T cells against melanoma-derived MAFs.
- To explore the mechanisms and factors influencing γδ T cell-mediated MAF killing.
Main Methods:
- An in vitro platform was established using primary Vδ2 γδ T cells and patient-derived MAFs.
- Zoledronic acid, anti-BTN3A1, anti-TCR γδ, and anti-BTN2A1 antibodies were used to modulate γδ T cell activity.
- Apoptosis induction in MAFs was assessed.
Main Results:
- Zoledronic acid (1-2.5 µM) was essential for inducing MAF apoptosis by γδ T cells.
- An anti-BTN3A1 antibody (clone 20.1) enhanced γδ T cell cytotoxicity against MAFs.
- Anti-TCR γδ and anti-BTN2A1 antibodies reduced this cytotoxic effect.
Conclusions:
- Activated γδ T cells can eliminate MAFs, suggesting a novel therapeutic avenue for melanoma.
- Zoledronic acid and specific antibody targeting (anti-BTN3A1) can enhance this anti-MAFF effect.
- Findings support further clinical investigation of γδ T cell-based melanoma therapies.
