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

CD8+ T cells in lung tumors differentiate through convergent pathways to an expanded and actively cycling terminal state. Tumor-infiltrating lymphocyte lessons The presence of intratumoral CD8+ tumor-infiltrating lymphocytes (TILs) is associated with better outcomes for patients with non–small cell lung cancer (NSCLC). These TILs consist of multiple subpopulations, and Gueguen et al. use single-cell RNA and T cell receptor sequencing to examine the origins and functional organization of TILs in NSCLC. They identified two precursor CD8+ TIL subpopulations with memory-like gene signatures. One of these subpopulations is detected in peripheral blood, whereas the other population is detected in juxtatumor tissue. Both subsets differentiate through a similar transitional stage into terminal effector TILs, which appear to be actively cycling within the tumor. Together, these results better define the origins and differentiation of CD8+ TILs associated with NSCLC. 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.