PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy
Daniel Davies, Shraddha Kamdar, Richard Woolf, Iva Zlatareva, Maria Luisa Iannitto, Cienne Morton, Yasmin Haque, H Martin, Dhruva Biswas, Susan Ndagire, Martina Munonyara, Cheryl Gillett, Olga O’Neill, Oliver Nussbaumer, Adrian Hayday, Yin Wu
Abstract
Abstract Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)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 functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1 + γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1 + cells, we show that PD-1 + Vδ1 + cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1 + CD8 + αβ T cells. In particular, PD-1 + Vδ1 + cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.