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

“Stem-like” TCF1⁺ CD8⁺ T (T_SL) 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 T_SL 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 T_SL 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 T_SL 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.