Vγ9Vδ2 T Cells Express an Antitumor Profile Associated with Anti–PD-(L)1 Responses and Activation Defects Restored by Anti-BTN3A in Triple-Negative Breast Cancer

Abstract Vγ9Vδ2 (TCRVγ9+ TCRVδ2+) T cells are promising immunotherapeutic targets with effective antitumor properties in both in vitro and preclinical models of triple-negative breast cancer (TNBC). However, no information about their potential role in the context of human TNBC progression and response to immunotherapy has been reported. One key reason for this is the scarcity of Vγ9Vδ2 T-cell infiltrates relative to their Vδ1 (TCRVδ1+) and αβCD8 (TCRαβ+ CD8αβ+) T-cell counterparts. We provide comprehensive single-cell profiling of Vγ9Vδ2 T cells from patients with TNBC, prior to and following PD-(L)1 blockade therapy. We report that baseline Vγ9Vδ2 T-cell infiltrate expressing a unique cytotoxic type I phenotype could be associated with improved survival in patients with TNBC. Vγ9Vδ2 T cells harboring characteristics of enhanced antitumor activity (KLRC1+) were further associated with improved response to PD-(L)1 blockade therapy in patients with TNBC. Vγ9Vδ2 T cells had low expression levels of T-cell exhaustion (PD-1LowTOXLow) and T-cell receptor signaling hallmarks compared with Vδ1 and αβCD8 T cells, along with skewed differentiation profiles toward early effector memory phenotypes, both before and after anti–PD-1 therapy in TNBC tumors. Consistently, we observed limited activity of anti–PD-1 on tumor-infiltrating Vγ9Vδ2 T cells. In vitro, the use of anti–butyrophilin-3A antibodies in addition to anti–PD-1 reinvigorated the cytotoxic type I functions of peripheral Vγ9Vδ2 T cells from patients with breast cancer. Together, these data provide a rationale for Vγ9Vδ2 T cell–based combination therapy in patients with TNBC.