A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade

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.