biostudies-literatureDavies DFrancis Crick InstituteTakeda Pharmaceutical CompanyMedical Research CouncilThe Francis Crick InstituteWellcome Trust420-432https://www.ebi.ac.uk/biostudies/studies/S-EPMC10965442biostudies-literatureUnknown5(3)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 Nature cancerPD-1 defines a distinct, functional, tissue-adapted state in Vδ1<sup>+</sup> T cells with implications for cancer immunotherapy.PMC10965442FC001093MR/K002627/1CC2012220589/Z/20/ZCC1064Zlatareva IHayday AIannitto MLMorton CO'Neill OGillett CMartin HMunonyara MKamdar SBiswas DNussbaumer OHaque YWoolf RNdagire SDavies DWu YfalsePD-1 defines a distinct, functional, tissue-adapted state in Vδ1<sup>+</sup> T cells with implications for cancer immunotherapy.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 2024-01-01T00:00:00Z2024 Mar2026-07-15T20:06:41.194Z2025-04-04T22:59:46.837ZS-EPMC109654423817234110.1038/s43018-023-00690-0