Exhausted intratumoral Vδ2 γδ T cells in human kidney cancer retain effector function.

Gamma delta (γδ) 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 Vδ2 γδ T cells, with equivalent representation of Vδ1 and Vδ1 cells, that are distinct from γδ T cells found in normal human tissues. These tumor-resident Vδ2 T cells can express the transcriptional program of exhausted αβ CD8 T cells as well as canonical markers of terminal T-cell exhaustion including PD-1, TIGIT and TIM-3. Although Vδ2 γδ T cells have reduced IL-2 production, they retain expression of cytolytic effector molecules and co-stimulatory receptors such as 4-1BB. Exhausted Vδ2 γδ T cells are composed of three distinct populations that lack TCF7, are clonally expanded and express cytotoxic molecules and multiple Vδ2 T-cell receptors. Human tumor-derived Vδ2 γδ T cells maintain cytotoxic function and pro-inflammatory cytokine secretion in vitro. The transcriptional program of Vδ2 T cells in pretreatment tumor biopsies was used to predict subsequent clinical responses to PD-1 blockade in patients with cancer. Thus, Vδ2 γδ T cells within the tumor microenvironment can contribute to antitumor efficacy.