Contribution of resident and circulating precursors to tumor-infiltrating CD8 + T cell populations in lung cancer

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Gueguen, Paul | Metoikidou, Christina | Dupic, Thomas | Lawand, Myriam | Goudot, Christel | Baulande, Sylvain | Lameiras, Sonia | Lantz, Olivier | Girard, Nicolas | Seguin-Givelet, Agathe | Lefevre, Marine | Mora, Thierry | Walczak, Aleksandra | Waterfall, Joshua | Amigorena, Sebastian

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. Tumor-infiltrating lymphocytes (TILs), in general, and especially CD8+ TILs, represent a favorable prognostic factor in non–small cell lung cancer (NSCLC). The tissue origin, regenerative capacities, and differentiation pathways of TIL subpopulations remain poorly understood. Using a combination of single-cell RNA and T cell receptor (TCR) sequencing, we investigate the functional organization of TIL populations in primary NSCLC. We identify two CD8+ TIL subpopulations expressing memory-like gene modules: one is also present in blood (circulating precursors) and the other one in juxtatumor tissue (tissue-resident precursors). In tumors, these two precursor populations converge through a unique transitional state into terminally differentiated cells, often referred to as dysfunctional or exhausted. Differentiation is associated with TCR expansion, and transition from precursor to late-differentiated states correlates with intratumor T cell cycling. These results provide a coherent working model for TIL origin, ontogeny, and functional organization in primary NSCLC

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