PD-1 and TIGIT co-expression identifies a circulating CD8 T cell population predictive of response to anti-PD-1 therapy in melanoma and Merkel-cell carcinoma patients [TCR-seq]

Clinical benefit from PD-1 inhibitors relies on reinvigoration of endogenous anti-tumor immunity. Efforts to define cellular populations associated with PD-1 clinical efficacy have been largely restricted to analysis of tumor material and the description of subsets of relevant cellular-based biomarkers in the blood of PD-1 inhibitor treated cancer patients are yet to be characterized. Given the particular expression pattern of PD-1 and TIGIT inhibitory receptors on peripheral CD8 T-cell subsets and the reported importance of CD8 T cells co-expressing these two markers for anti-PD-1 efficacy, we sought to determine the distinct biological features of peripheral CD8 subsets delineated based on PD-1 and TIGIT expression. Our findings identify the PD-1+TIGIT+ (DPOS) CD8+ T-cell population as a subset of highly activated and proliferating T cells, enriched in tumor-specific T-cell clones and overexpressing CXCR5, a key marker of the recently described CD8 cytotoxic follicular T cell (Tfc) population. Strikingly, the frequency of DPOS T cells after 1 month of anti-PD-1 therapy was associated with clinical response in three independent cohorts of cancer patients treated with PD-1 inhibitor. Additionally, transcriptomic profiling of this subset described common features with the PD-1high CXCL13+ lymphocyte subset previously demonstrated in tumor infiltrates to be predictive of PD-1 blockade efficacy. Furthermore, TCR repertoire analysis described a cluster of emerging T-cell clonotypes in the DPOS population as a key feature of PD-1 therapeutic efficacy. Overall design: Four CD8 T cell populations flow sorted according to differential PD-1 and TIGIT expression patterns (PD-1negTIGITneg: thereafter called DNEG, PD-1posTIGITneg: thereafter called PD1, PD-1posTIGITpos thereafter called DPOS, PD-1negTIGITpos thereafter called TIGIT) before total RNA extraction at baseline and after 1 or 2 months of PD-1 therapy (TCRseq, 12 patients).