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.
Bibliographical noteFunding Information:
We acknowledge the University of Minnesota Flow Cytometry Core and Research Animal Resource facility. M.T.P. is supported by an AHA predoctoral fellowship ( 903380 ). Z.C.S. is supported by a NIH T32 AG029796 followed by NIH F31CA275289 . M.M.F. was supported by the Ministry of Science and Higher Education of the Russian Federation (agreement 075-15-2022-301 ). K.Z. was supported by the Priority 2030 Federal Academic Leadership Program . J.W.W. is supported by NIH R01AI165553 and AHA CDA 855022 . I.M.S. is supported by NIH R01CA249393 , R01CA255039 , and P01CA254849 ; Department of Defense PA200286 ; a PanCAN-AACR Catalyst Award ( 19-35-STRO ); and an American Cancer Society Institutional Research Grant ( 124166-IRG-58-001-55-IRG65 ).
© 2023 The Author(s)
- CD4 T cells
- CP: Cancer
- CP: Immunology
- T cells
- pancreatic cancer