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