title: Cell-extrinsic effects of tumor ER stress imprint myeloid dendritic cells and impair CD8⁺ T cell priming.
abstract: Tumor-infiltrating myeloid cells, such as dendritic cells (BMDC), are key regulators of tumor growth. However, the tumor-derived signals polarizing BMDC to a phenotype that subverts cell-mediated anti-tumor immunity have yet to be fully elucidated. Addressing this unresolved problem we show that the tumor unfolded protein response (UPR) can function in a cell-extrinsic manner via the transmission of ER stress (TERS) to BMDC. TERS-imprinted BMDC upregulate the production of pro-inflammatory, tumorigenic cytokines but also the immunosuppressive enzyme arginase. Importantly, they downregulate cross-presentation of high-affinity antigen and fail to effectively cross-prime CD8(+) T cells, causing T cell activation without proliferation and similarly dominantly suppress cross-priming by bystander BMDC. Lastly, TERS-imprinted BMDC facilitate tumor growth in vivo with fewer tumor-infiltrating CD8(+) T cells. In sum, we demonstrate that tumor-borne ER stress imprints ab initio BMDC to a phenotype that recapitulates several of the inflammatory/suppressive characteristics ascribed to tumor-infiltrating myeloid cells, highlighting the tumor UPR as a critical controller of anti-tumor immunity and a new target for immune modulation in cancer.
authors.affiliation: The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Navin R
authors.initials: NR
authors.lastname: Mahadevan
authors.forename: Veronika
authors.initials: V
authors.lastname: Anufreichik
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rodvold
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Chiu
authors.forename: Homero
authors.initials: H
authors.lastname: Sepulveda
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zanetti
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism*; D047368:Tumor Burden