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While immune responses against primary tumors are critically important, T cells must also be capable of functioning at sites where cancers metastasize. Here we investigated how resident memory (TRM) and circulating memory (TCIRCM) CD8 T cells potentiate immunity to cancer in diverse tissue microenvironments. Based on a mouse model of immunity to melanoma with associated autoimmune vitiligo, we show that tumor-specific memory T cells are capable of forming a widespread network of transcriptionally distinct subsets, throughout lymphoid tissues and visceral organs. Among these, we discovered a population of TRM cells that reside durably within LNs, where they protect against invading melanoma cells. These LN-resident memory (LN TRM) cells adopt a transcriptional program that is distinct from TRM cells in other tissues, and which uniquely predicts survival in melanoma patients with regional LN metastases. This work reveals a novel role for TRM cells in durable immunity to cancer at crucial sites of metastasis.

Summary The nature of the anti-tumor immune response changes as primary tumors progress and metastasize. We investigated the role of resident memory (Trm) and circulating memory (Tcirm) cells in anti-tumor responses at metastatic locations using a mouse model of melanoma-associated vitiligo. We found that the transcriptional characteristics of tumor-specific CD8+ T cells were defined by the tissue of occupancy. Parabiosis revealed that tumor-specific Trm and Tcirm compartments persisted throughout visceral organs, but Trm cells dominated lymph nodes (LNs). Single-cell RNA-sequencing profiles of Trm cells in LN and skin were distinct, and T cell clonotypes that occupied both tissues were overwhelmingly maintained as Trm in LNs. Whereas Tcirm cells prevented melanoma growth in the lungs, Trm afforded long-lived protection against melanoma seeding in LNs. Expanded Trm populations were also present in melanoma-involved LNs from patients, and their transcriptional signature predicted better survival. Thus, tumor-specific Trm cells persist in LNs, restricting metastatic cancer.