Tissue-resident memory CD8+ T cells amplify anti-tumor immunity by triggering antigen spreading through dendritic cells

• Published in: Nature communications Vol. 10; no. 1; pp. 4401 - 12
• Main Authors: Menares, Evelyn, Gálvez-Cancino, Felipe, Cáceres-Morgado, Pablo, Ghorani, Ehsan, López, Ernesto, Díaz, Ximena, Saavedra-Almarza, Juan, Figueroa, Diego A., Roa, Eduardo, Quezada, Sergio A., Lladser, Alvaro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.09.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 631/250/2152/1566/1571; 631/250/2504/133; 631/250/251/1567; 631/67/1813/1634; 631/67/580; 64/60; Adaptive immunity; Amplification; Animals; Antigens; Antigens - immunology; Autoantigens; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell Movement - immunology; Cross-Priming - immunology; Crosstalk; Cytotoxicity; Dendritic cells; Dendritic Cells - immunology; Drainage; Epitopes; Gene sequencing; Humanities and Social Sciences; Humans; Immunity; Immunologic Memory - immunology; Immunological memory; Lymph nodes; Lymph Nodes - immunology; Lymphocytes; Lymphocytes T; Melanoma; Melanoma - immunology; Melanoma - pathology; Memory cells; Mice, Inbred C57BL; Mice, Transgenic; multidisciplinary; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Skin; Skin - cytology; Skin - immunology; Solid tumors; T-Lymphocytes, Cytotoxic - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12319-x

Tissue-resident memory CD8 + T (Trm) cells mediate potent local innate and adaptive immune responses and play a central role against solid tumors. However, whether Trm cells cross-talk with dendritic cells (DCs) to support anti-tumor immunity remains unclear. Here we show that antigen-specific activation of skin Trm cells leads to maturation and migration to draining lymph nodes of cross-presenting dermal DCs. Tumor rejection mediated by Trm cells triggers the spread of cytotoxic CD8 + T cell responses against tumor-derived neo- and self-antigens via dermal DCs. These responses suppress the growth of intradermal tumors and disseminated melanoma lacking the Trm cell-targeted epitope. Moreover, analysis of RNA sequencing data from human melanoma tumors reveals that enrichment of a Trm cell gene signature associates with DC activation and improved survival. This work unveils the ability of Trm cells to amplify the breath of cytotoxic CD8 + T cell responses through DCs, thereby strengthening anti-tumor immunity. Immunotherapy can induce antigen spreading of antitumor T cell response, which correlates with better outcomes. Here the authors show that tissue-resident memory CD8 T cells promote antigen spreading via lysing tumor cells and promoting their uptake and cross-presentation by dendritic cells, thereby eliciting de novo T cell responses.