The features of circulating and tumor-infiltrating γδ T cells in melanoma patients display critical perturbations with prognostic impact on clinical outcome

gamma delta T cells hold a pivotal role in tumor immunosurveillance through their prompt activation and cytokine secretion, their ability to kill tumor cells in an Human Leukocyte Antigen (HLA)-unrestricted manner, and their combination of features of both innate and adaptive immunity. These unique properties and functional plasticity render them very attractive both as targets and vectors for cancer immunotherapy. Yet, these potent and fascinating antitumor effectors have not been extensively explored in melanoma. We provided here a detailed investigation of the phenotypic and functional properties of circulating and tumor-infiltrating gamma delta T cells in melanoma patients, and their impact on clinical evolution. High proportions of circulating- and tumor-infiltrating gamma delta T and delta 2+ subset were associated with better clinical outcome. We reported however that circulating and tumor-infiltrating gamma delta T cells from melanoma patients displayed an altered expression of NCR, KIR, and immune checkpoints, and identified NKp44, PD1, 41BB/41BBL, TIM3, and LAG3 as crucial checkpoints allowing immune escape and tumor progression. Notably, melanoma drastically impaired the ability of gamma delta T cells to exhibit activation molecules, secrete cytokines, and display cytotoxicity toward melanoma in response to stimulation with phosphoantigens. It drove them toward regulatory and Th17 profiles associated with poor clinical outcomes. Our study highlights that melanoma hijacked gamma delta T cells to escape from immune control, and revealed that circulating and tumor-infiltrating gamma delta T cell features are promising potential biomarkers of clinical evolution. Such understanding of the physiopathology of gamma delta T cells may help designing new therapeutic approaches exploiting the antitumor potential of gamma delta T cells while counteracting their skewing by tumors to improve patient outcomes.