부산대학교 도서관

Evidence from mouse chronic viral infection models suggests that CD8+T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8+T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1–) from non-small-cell lung cancer patients. PD-1TT cells showed a markedly different transcriptional and metabolic profile from PD-1Nand PD-1–lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1Tlymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1Tcells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention. Tumor-infiltrating CD8+T cells with high expression of PD-1 in non-small-cell lung cancer are distinct from exhausted T cells in chronic virus infection, have high tumor reactivity and associate with response to PD-1-targeted immunotherapy.