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-1T), intermediate (PD-1N) and no PD-1 expression (PD-1) from non-small-cell lung cancer patients. PD-1T T cells showed a markedly different transcriptional and metabolic profile from PD-1N and PD-1 lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T 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-1T 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.

Daniela S. Thommen, Viktor H. Koelzer, Petra Herzig, Andreas Roller, Marcel Trefny, Sarah Dimeloe, Anna Kiialainen, Jonathan Hanhart, Catherine Schill, Christoph Hess, Spasenija Savic Prince, Mark Wiese, Didier Lardinois, Ping-Chih Ho, Christian Klein, Vaios Karanikas, Kirsten D. Mertz, Ton N. Schumacher & Alfred Zippelius


Nature Medicine | Published June 11th, 2018 | DOI https://doi.org/10.1038/s41591-018-0057-z