Tumor resistance mechanisms and their consequences on γδ T cell activation.

Human γδ T lymphocytes are predominated by two major subsets, defined by the variable domain of the δ chain. Both, Vδ1 and Vδ2 T cells infiltrate in tumors and have been implicated in cancer immunosurveillance. Since the localization and distribution of tumor-infiltrating γδ T cell subsets and their impact on survival of cancer patients are not completely defined, this review summarizes the current knowledge about this issue. Different intrinsic tumor resistance mechanisms and immunosuppressive molecules of immune cells in the tumor microenvironment have been reported to negatively influence functional properties of γδ T cell subsets. Here, we focus on selected tumor resistance mechanisms including overexpression of cyclooxygenase (COX)-2 and indolamine-2,3-dioxygenase (IDO)-1/2, regulation by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-R4 pathway and the release of galectins. These inhibitory mechanisms play important roles in the cross-talk of γδ T cell subsets and tumor cells, thereby influencing cytotoxicity or proliferation of γδ T cells and limiting a successful γδ T cell-based immunotherapy. Possible future directions of a combined therapy of adoptively transferred γδ T cells together with γδ-targeting bispecific T cell engagers and COX-2 or IDO-1/2 inhibitors or targeting sialoglycan-Siglec pathways will be discussed and considered as attractive therapeutic options to overcome the immunosuppressive tumor microenvironment.