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

Abstract

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.

Inhibiting the Unconventionals: Importance of Immune Checkpoint Receptors in γδ T, MAIT, and NKT Cells

“…It has been reported that the inhibitory function of LAG-3 is correlated with its expression levels on the cell surface [ 117 ]. In a recent study, melanoma patients showed higher proportions of both circulating and tumor-infiltrating γδ T cells expressing LAG-3 compared to control groups, suggesting that LAG-3 may be crucial for immune escape and tumor progression by inhibition of γδ T cells [ 121 ]. Furthermore, the expression of LAG-3 in tumor-infiltrating γδ T cells was associated with earlier relapse and shorter overall survival [ 121 ].…”

“…In a recent study, melanoma patients showed higher proportions of both circulating and tumor-infiltrating γδ T cells expressing LAG-3 compared to control groups, suggesting that LAG-3 may be crucial for immune escape and tumor progression by inhibition of γδ T cells [ 121 ]. Furthermore, the expression of LAG-3 in tumor-infiltrating γδ T cells was associated with earlier relapse and shorter overall survival [ 121 ]. More detailed studies on the putative role of LAG-3 in γδ T cells in the context of cancer are lacking.…”

Nanomedicines as Multifunctional Modulators of Melanoma Immune Microenvironment

“…Therefore, the skewed melanoma microenvironment is able to impair the anti‐tumor function of γδ T cells to escape immunosurveillance. [ 84 ]…”

Gamma Delta T Cells and Their Pathogenic Role in Psoriasis

“…Relative to αβT cells, γδT cells have been less studied and characterized. It is becoming clear that γδT cells are heterogeneous populations of cells with multifunctional capacities in repairing host tissue ( 6 ), pathogen clearance ( 7 ), tumor surveillance ( 8 , 9 ), and proinflammatory effects ( 10 ).…”