Tumor-specific CD4 T cells instruct monocyte fate in pancreatic ductal adenocarcinoma.

Autor:	Patterson MT; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA., Burrack AL; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA., Xu Y; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA., Hickok GH; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA., Schmiechen ZC; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA., Becker S; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA., Cruz-Hinojoza E; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA., Schrank PR; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA., Kennedy AE; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA., Firulyova MM; Computer Technologies Laboratory, ITMO University, Saint-Petersburg, Russia; National Medical Research Center, Saint-Petersburg, Russia., Miller EA; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA., Zaitsev K; Computer Technologies Laboratory, ITMO University, Saint-Petersburg, Russia., Williams JW; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA. Electronic address: jww@umn.edu., Stromnes IM; Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Masonic Cancer Center and University of Minnesota Medical School, Minneapolis, MN 55414, USA; Center for Genome Engineering, University of Minnesota Medical School, Minneapolis, MN 55414, USA. Electronic address: ingunn@umn.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Jul 25; Vol. 42 (7), pp. 112732. Date of Electronic Publication: 2023 Jul 03.
DOI:	10.1016/j.celrep.2023.112732
Abstrakt:	Pancreatic ductal adenocarcinoma (PDA) orchestrates a suppressive tumor microenvironment that fosters immunotherapy resistance. Tumor-associated macrophages (TAMs) are the principal immune cell infiltrating PDA and are heterogeneous. Here, by employing macrophage fate-mapping approaches and single-cell RNA sequencing, we show that monocytes give rise to most macrophage subsets in PDA. Tumor-specific CD4, but not CD8, T cells promote monocyte differentiation into MHCII hi anti-tumor macrophages. By conditional major histocompatibility complex (MHC) class II deletion on monocyte-derived macrophages, we show that tumor antigen presentation is required for instructing monocyte differentiation into anti-tumor macrophages, promoting Th1 cells, abrogating Treg cells, and mitigating CD8 T cell exhaustion. Non-redundant IFNγ and CD40 promote MHCII hi anti-tumor macrophages. Intratumoral monocytes adopt a pro-tumor fate indistinguishable from that of tissue-resident macrophages following loss of macrophage MHC class II or tumor-specific CD4 T cells. Thus, tumor antigen presentation by macrophages to CD4 T cells dictates TAM fate and is a major determinant of macrophage heterogeneity in cancer. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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