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

Michael T. Patterson; Adam L. Burrack; Yingzheng Xu; Grant H. Hickok; Zoe C. Schmiechen; Samuel Becker; Eduardo Cruz-Hinojoza; Patricia R. Schrank; Ainsley E. Kennedy; Maria M. Firulyova; Ebony A. Miller; Konstantin Zaitsev; Jesse W. Williams; Ingunn M. Stromnes

Cell Reports (Jul 2023)

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

Michael T. Patterson,
Adam L. Burrack,
Yingzheng Xu,
Grant H. Hickok,
Zoe C. Schmiechen,
Samuel Becker,
Eduardo Cruz-Hinojoza,
Patricia R. Schrank,
Ainsley E. Kennedy,
Maria M. Firulyova,
Ebony A. Miller,
Konstantin Zaitsev,
Jesse W. Williams,
Ingunn M. Stromnes

Affiliations

Michael T. Patterson: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
Adam L. Burrack: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Yingzheng Xu: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
Grant H. Hickok: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Zoe C. Schmiechen: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Samuel Becker: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Eduardo Cruz-Hinojoza: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Patricia R. Schrank: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
Ainsley E. Kennedy: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA
Maria M. Firulyova: Computer Technologies Laboratory, ITMO University, Saint-Petersburg, Russia; National Medical Research Center, Saint-Petersburg, Russia
Ebony A. Miller: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA
Konstantin Zaitsev: Computer Technologies Laboratory, ITMO University, Saint-Petersburg, Russia
Jesse W. Williams: Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA; Corresponding author
Ingunn M. Stromnes: 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; Corresponding author

Journal volume & issue: Vol. 42, no. 7
p. 112732

Abstract

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Summary: 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 MHCIIhi 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 MHCIIhi 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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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