Patterson et al. used scRNAseq and monocyte fate-mapping methods to study crosstalk between macrophages (Mψ) and tumor-specific CD4+ T cells in pancreatic ductal adenocarcinoma (PDA). In an orthotopic mouse model, tumor-specific CD4+, but not CD8+ T cells drove monocyte differentiation into antitumor MHC-IIhi macrophages through cognate antigen presentation by Mψ and downstream IFNγ and CD40:CD40L pathways. Most Mψ subsets in the PDA TME were derived from monocyte differentiation. Loss of either MHC-II or CD4+ T cells promoted monocyte differentiation toward alternatively activated states that stimulated tumor progression.
Contributed by Katherine Turner
ABSTRACT: 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 IFN_ 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.
Author Info: (1) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, US
Author Info: (1) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA. (2) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA. (3) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA. (4) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA. (5) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA. (6) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA. (7) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA. (8) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA. (9) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55414, USA. (10) Computer Technologies Laboratory, ITMO University, Saint-Petersburg, Russia; National Medical Research Center, Saint-Petersburg, Russia. (11) Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55414, USA. (12) Computer Technologies Laboratory, ITMO University, Saint-Petersburg, Russia. (13) 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. (14) 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.
