Abstract

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-1^T), intermediate (PD-1^N) and no PD-1 expression (PD-1^–) from non-small-cell lung cancer patients. PD-1^T T cells showed a markedly different transcriptional and metabolic profile from PD-1^N and PD-1^– lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1^T lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1^T cells 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.