Resident memory (T-RM) cells sustain immunity to cancer at sites of frequent metastasis

Abstract Tissue resident memory T cells (TRM cells) have recently been recognized as durable mediators of immunity to cancer. We previously showed that regulatory T cell-depleting immunotherapy of B16 melanoma induces protective TRM cells that persist in the skin of mice that develop autoimmune vitiligo. The goal of the present study was to assess the host-wide diversity and function of memory CD8 T cells throughout peripheral tissues of these mice. Using Pmel transgenic CD8 T cells to track Ag-specific responses revealed the generation of memory T cells with a TRM-like phenotype (CD44hi CD62Llow CD103+CD69+) throughout skin, lungs and liver. Parabiotic transfer/equilibration experiments demonstrated the presence of TRM cells in each peripheral tissue and also, surprisingly, in tumor-draining lymph nodes. Tumor protection experiments in parabiotic mice, and after treatment with the S1PR antagonist FTY720, indicated roles for both TRM cells and circulating memory T cells in providing long-lived protection against melanoma re-challenge at various tissue locations. Single-cell transcriptional profiling of memory CD8 T cells isolated from the skin, lungs, liver, lymph nodes, and spleen indicated the presence of diverse populations with features of both circulating and resident memory, but with TRM cell populations dominating in peripheral tissues and tumor-draining lymph nodes. Moreover, clonally-identical TRM cells in the skin, liver, lungs, and lymph nodes each possessed unique transcriptional features exclusive to their tissue of origin. These studies highlight the tissue-specific adaptations of tumor-reactive TRM cells, and the importance of host-wide TRM responses in providing immunity to cancer.