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

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish (US)
Article number112732
JournalCell reports
Volume42
Issue number7
DOIs
StatePublished - Jul 25 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Keywords

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

Fingerprint

Dive into the research topics of 'Tumor-specific CD4 T cells instruct monocyte fate in pancreatic ductal adenocarcinoma'. Together they form a unique fingerprint.

Cite this