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A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response

Description Tumor-specific CD8+ T cells in stable tumor-draining lymph node reservoir are clonally and developmentally related to those in tumors. A niche in the node The presence of “stem-like” TCF1+ CD8+ T (TSL) cells in tumors correlates with better patient outcomes after immunotherapy. TSL cells undergo terminal differentiation and exhaustion in the tumor microenvironment; therefore, how a stem-like population is maintained throughout tumor development is unclear. Using a mouse model of lung adenocarcinoma programmed to express neoantigens, Connolly et al. identified a stable reservoir of tumor-specific TSL cells in the tumor-draining lymph node (dLN). TSL cells migrated from the dLN to the tumor, where they became terminally differentiated as the tumor microenvironment shifted from “hot” to “cold.” These findings suggest that therapeutic strategies directed at tumor-specific T cells in the dLN may be a promising approach to treat patients with cold tumors. “Stem-like” TCF1+ CD8+ T (TSL) cells are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy, but, as tumors contain signals that should drive T cell terminal differentiation, how these cells are maintained in tumors remains unclear. In this study, we found that a small number of TCF1+ tumor-specific CD8+ T cells were present in lung tumors throughout their development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from “hot” (T cell inflamed) to “cold” (non–T cell inflamed). By contrast, most tumor-specific CD8+ T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSL from chronic lymphocytic choriomeningitis virus infection, and this population was stable over time despite the changes in the TME. dLN T cells were the developmental precursors of, and were clonally related to, their more differentiated intratumoral counterparts. Our data support the hypothesis that dLN T cells are the developmental precursors of the TCF1+ T cells in tumors that are maintained by continuous migration. Last, CD8+ T cells similar to TSL were also present in LNs from patients with lung adenocarcinoma, suggesting that a similar model may be relevant in human disease. Thus, we propose that the dLN TSL reservoir has a critical function in sustaining antitumor T cells during tumor development and in protecting them from the terminal differentiation that occurs in the TME.