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

ABSTRACT: “Stem-like” TCF1+ CD8+ T cells (TSL) 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 LCMV 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 which are maintained by continuous migration. Finally, CD8+ T cells similar to TSL were also present in LNs from lung adenocarcinoma patients, suggesting 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 protecting them from the terminal differentiation that occurs in the TME. Methods: We analyzed single-cell RNA-sequencing to assess the differentiation state and trajectory of the cell subsets present after FACs sorting on endogenous GP33-specific CD8+ T cells from tumors and draining lymph nodes of tumor-bearing KP-NINJA mice, comparing them to GP33-specific CD8+ T cells from spleens of mice infected with acute or chronic LCMV. In order to determine the clonal relationship of these cells from tumors and draining lymph nodes, we analyzed paired single-cell TCR sequencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE182509 | GEO | 2021/08/27

REPOSITORIES: GEO