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

Cell Rep. 2023 Jul 25;42(7):112732. doi: 10.1016/j.celrep.2023.112732. Epub 2023 Jul 3.

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 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.

Keywords: CCR2; CD4 T cells; CD40; CP: Cancer; CP: Immunology; IFNg; PD-L1; PDA; T cells; immunotherapy; macrophage; pancreatic cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm
  • CD4-Positive T-Lymphocytes
  • Carcinoma, Pancreatic Ductal* / genetics
  • Histocompatibility Antigens Class II
  • Humans
  • Monocytes
  • Pancreatic Neoplasms* / pathology
  • Tumor Microenvironment

Substances

  • Antigens, Neoplasm
  • Histocompatibility Antigens Class II