Resident memory CD8+ T cells in regional lymph nodes mediate immunity to metastatic melanoma

• Published in: Immunity (Cambridge, Mass.) Mass.), 2021-09, Vol.54 (9), p.2117-2132.e7
• Main Authors: Molodtsov, Aleksey K., Khatwani, Nikhil, Vella, Jennifer L., Lewis, Kathryn A., Zhao, Yanding, Han, Jichang, Sullivan, Delaney E., Searles, Tyler G., Preiss, Nicholas K., Shabaneh, Tamer B., Zhang, Peisheng, Hawkes, Aaron R., Malik, Brian T., Kolling, Fred W., Usherwood, Edward J., Wong, Sandra L., Phillips, Joseph D., Shirai, Keisuke, Angeles, Christina V., Yan, Shaofeng, Curiel, Tyler J., Huang, Yina H., Cheng, Chao, Turk, Mary Jo
• Format: Article
• Language: English
• Subjects: Animals; Cancer; CD69; CD8 T cells; CD8-Positive T-Lymphocytes - immunology; CXCR6; Humans; Immunologic Memory - immunology; Lymph Nodes - immunology; Melanoma - immunology; Melanoma, Cutaneous Malignant; Melanoma, Experimental - immunology; Mice; parabiosis; scRNA-seq; Skin Neoplasms - immunology; TCR; Trm; TRP-2; Vitiligo
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.08.019

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. [Display omitted] •Tissue localization defines the transcriptional profile of tumor-specific CD8+ T cells•Melanoma-specific Trm populations develop in skin-draining lymph nodes•Trm cells protect against melanoma tumor seeding in lymph nodes•A lymph node Trm transcriptional signature uniquely predicts survival in melanoma patients Lymph nodes (LNs) are frequent sites of metastasis. Molodtsov, Khatwani et al. find that melanoma-specific CD8+ T cells persist as functional resident memory (Trm) populations within skin-draining LNs, and these Trm cells prevent melanoma growth upon tumor seeding in LNs. A LN Trm transcriptional signature predicts survival in melanoma patients, highlighting the relevance of LN Trm function in human disease.