γδT 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 γδT cells in
melanoma patients, and their impact on clinical evolution. High proportions of circulating- and
tumor-infiltrating γδT and δ2+ subset were associated with better clinical outcome. We reported however that circulating and
tumor-infiltrating γδT 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 γδT 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 γδT cells to escape from immune control, and revealed that circulating and
tumor-infiltrating γδT cell features are promising potential
biomarkers of clinical evolution. Such understanding of the physiopathology of γδT cells may help designing new therapeutic approaches exploiting the antitumor potential of γδT cells while counteracting their skewing by
tumors to improve patient outcomes.