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

摘要

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. We observed that, PD-1^T T cells show a markedly different transcriptional and metabolic profile as compared to PD-1^N and PD-1^- lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1^T lymphocytes are impaired in classical effector cytokine production, they produce CXCL13 that 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 novel potential avenues for therapeutic intervention.