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

By D. Thommen, V. Koelzer, P. Herzig, A. Roller, Marcel P. Trefny, Sarah Dimeloe, A. Kiialainen, Jonathan Hanhart, Catherine Schill, C. Hess and 9 more. Nature Medicine, 2018

1,018 citations recorded by the source corpus.

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. 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/9dc8a4f704857a73aa546456b470efb7a11709e7

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Citations in the corpus

Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020, background): “Similar effector and exhausted T cells, which have the highest proliferative capacity among T cell subsets, were observed in other cancers (Figure S4C) (Guo et al., 2018; Li et al., 2019; Savas et al., 2018; Thommen et al., 2018; Tirosh et al., 2016a; Zheng et al., 2017).”
CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment (2019, background): “In a recent analysis of varied NSCLC patient samples, a population of CD8 TILs with high PD-1 expression did not appear exhausted, and genes involved in cycling and proliferation such as Ki-67, as well as genes involved in trafficking and metabolism, were upregulated (147).”
Tertiary lymphoid structures in cancer (2022, background): “With respect to the effect of conventional therapies on TLS formation, induction of TLSs has been observed after neoadjuvant chemotherapy in NSCLC (145) and hepatoblastoma related to APC mutations (146).”
Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition (2021, positive): “We note this result validates recent work from Thommen et al. (2018), and taken together, highlights that CXCL13 expression may be a feature of clonal neoantigen-reactive CD8 TILs that associates with CPI outcome in a pan-cancer cohort.”