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.