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

Evelyn Menares,Diego A Figueroa,Juan Saavedra-Almarza,Alvaro Lladser,Ximena Díaz,Ehsan Ghorani,Sergio A Quezada,Pablo Cáceres-Morgado,Ernesto López,Felipe Gálvez-Cancino,Eduardo Roa

doi:10.1038/s41467-019-12319-x

Abstract

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.

Highlights

Tissue-resident memory CD8+ T (Trm) cells mediate potent local innate and adaptive immune responses and play a central role against solid tumors
We observed that skin XCR1+ conventional type 1 dendritic cells (DCs), known as dermal DCs or DDCs (Fig. 1c) upregulated CD80, CD86, MHC class II and IL-12 molecules 24 h after Trm cell activation (Fig. 1d–g)
These data indicate that Trm cells induce maturation of dermal DCs, which are specialized in antigen cross-presentation and priming of CD8+ T cells[38]

Summary

Introduction

Tissue-resident memory CD8+ T (Trm) cells mediate potent local innate and adaptive immune responses and play a central role against solid tumors. Tumor-specific CTL responses are initiated at secondary lymphoid organs when naïve CD8+ T cells are activated by mature migratory dendritic cells (DCs) presenting tumor-derived antigens on MHC class I molecules[1,2]. Tissue adaptation-related features and enhanced cytotoxicity may contribute to the superior protective potential of Trm cells in human solid cancers. Complementary to their cytotoxic activity, Trm cells secrete large amounts of effector molecules, most prominently IFN-γ and TNF-α, which can activate other immune cells with anti-tumor potential. We hypothesized that Trm cells cooperate with DCs to support anti-tumor immunity by initiating secondary T-cell responses against tumor-derived antigens

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Results

Conclusion