Exhausted intratumoral V delta 2(-) gamma delta T cells in human kidney cancer retain effector function

Gamma delta (gamma delta) T cells reside within human tissues including tumors, but their function in mediating antitumor responses to immune checkpoint inhibition is unknown. Here we show that kidney cancers are infiltrated by V delta 2(-) gamma delta T cells, with equivalent representation of V delta 1(+) and V delta 1(-) cells, that are distinct from gamma delta T cells found in normal human tissues. These tumor-resident V delta 2(-) T cells can express the transcriptional program of exhausted alpha beta CD8(+) T cells as well as canonical markers of terminal T-cell exhaustion including PD-1, TIGIT and TIM-3. Although V delta 2(-) gamma delta T cells have reduced IL-2 production, they retain expression of cytolytic effector molecules and co-stimulatory receptors such as 4-1BB. Exhausted V delta 2(-) gamma delta T cells are composed of three distinct populations that lack TCF7, are clonally expanded and express cytotoxic molecules and multiple V delta 2(-) T-cell receptors. Human tumor-derived V delta 2(-) gamma delta T cells maintain cytotoxic function and pro-inflammatory cytokine secretion in vitro. The transcriptional program of V delta 2(-) T cells in pretreatment tumor biopsies was used to predict subsequent clinical responses to PD-1 blockade in patients with cancer. Thus, V delta 2(-) gamma delta T cells within the tumor microenvironment can contribute to antitumor efficacy. gamma delta T cells contribute to cancer immunity by killing tumor cells, but their function in the context of immune checkpoint inhibition is less clear. Here the authors show that a V delta 2(-) subset of gamma delta T cells in human kidney tumors phenotypically resembles exhausted T cells yet retains this cytolytic function and can be used to predict response to immune checkpoint inhibition.