PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy

Checkpoint inhibition (CPI), particularly that targeting the inhibitory co-receptor, programmed cell death protein (PD-1), has transformed cancer care. Although CPI can de repress cancer antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings γδ T cells have been implicated, but the immunological significance of PD-1 expression by tissue associated human Vδ1+ cells remains uncharacterised. Here we demonstrate that a transcriptional signature of intratumoral Vδ1+ cells predicts response to anti-PD-1 in patients with melanomas of relatively low neoantigen load. Moreover, by employing a protocol yielding substantial numbers of human skin γδ cells, we show that PD-1+ Vδ1+ cells display a transcriptomic programme of tissue-residence, survival/self-renewal, and functional competence distinct from the canonical exhaustion programme of co-located PD- 1+ CD8+ αβ T cells. Indeed, skin PD-1+ Vδ1+ cells retained effector responses to T cell receptor signalling that were inhibitable by PD-1 engagement and partially derepressed by CPI. The biological and therapeutic implications are both discussed. In the study presented here, 785 human genes were profiled using NanoString's nCounter Immune Exhaustion Panel in FACS sorted PD1+ CD8 T cells (n=6 biological replicates/group), PD1- CD8 T cells (n=9 biological replicates/group), Vd1+ PD1+ gamma delta T cells (n=8 biological replicates/group) and Vd1+ PD1- gamma delta T cells (n=8 biological replicates/group) obtained from human skin samples cultured for a total of 6 weeks in human IL-2 and IL-15 (3 weeks 'on grid' isolation phase and 3 weeks 'off grid' expansion phase. See growth protocol described in line 77 for details).