A Reservoir of Stem-Like CD8 T Cells in the Tumor-Draining Lymph Node Maintains the Ongoing Anti-Tumor Immune Response

Abstract

Intratumoral stem-like CD8+ T cells (T_SL) are necessary for immunotherapeutic efficacy. Yet, tumors are rich in signals driving terminal differentiation of T_SL cells into exhausted T cells. Using the “KP-NINJA” lung tumor model, we determined that tumor-specific T_SL cells terminally differentiate in tumors, but that they are maintained by a reservoir of T_SL cells from the tumor-draining lymph node (dLN). By tracing clones of tumor-specific CD8+ T cells using single-cell RNA/TCRseq, we found that dLN T_SL cells were the developmental precursors of the more differentiated intratumoral T cell populations. Moreover, dLN T_SL cells were developmentally stable over the disease course and blocking egress from dLNs resulted in a decrease in intratumoral T_SL cells. Thus, we propose that the dLN reservoir protects the overall tumor-specific T cell population from terminal differentiation, allowing for prolonged responses under conditions of chronic antigen exposure. Future immunotherapeutic strategies could leverage this reservoir for anti-tumor effects.