Tumor-infiltrating γδ T cells as targets of immune checkpoint blockade in melanoma

Melanoma is one of the most sensitive tumors to immune modulation, and the major challenge for melanoma patients' survival is immune checkpoint inhibitor (ICI) therapy. gamma delta T lymphocytes play an antitumoral role in a broad variety of tumors including melanoma and they are optimal candidates for cellular immunotherapy. Thus, a comprehensive analysis of the correlation between gamma delta T cells and immune checkpoint receptors in the context of melanoma was conducted, with the aim of devising an innovative combined immunotherapeutic strategy. In this study, using the GEPIA2.0 database, a significant positive correlation was observed between the expression of gamma delta T cell-related genes (TRGC1, TRGC2, TCRD) and immune checkpoint genes (PDCD1, HAVCR2, LAG3), highlighting the potential role of gamma delta T cells in the immune response within melanoma. Moreover, flow cytometry analysis unveiled a significant augmentation in the population of gamma delta T cells within melanoma lesions, which exhibited the expression of immune checkpoint receptors including LAG3, TIM3, and PD1. Analysis of single-cell RNA sequencing data revealed a significant enrichment and functional reprogramming of gamma delta T cell clusters in response to ICIs. Interestingly, the effects of ICI therapy varied between V delta 1 and V delta 2 gamma delta T cell subsets, with distinct changes in gene expression patterns. Last, a correlation analysis between gamma delta T cell abundance, immune checkpoint gene expression, and clinical outcomes in melanoma patients showed that low expression of immune checkpoint genes, including LAG3, HAVCR2, and PDCD1, was associated with improved 1-year overall survival, emphasizing the significance of these genes in predicting patient outcomes, potentially outweighing the impact of gamma delta T cell abundance. This study offers critical insights into the dynamic interaction between gamma delta T cells, immune checkpoint receptors, and melanoma, providing valuable perspectives for potential therapeutic avenues and predictive markers in this intricate interplay.