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

• DOI: 10.1016/j.celrep.2023.112732
• Publication Date: 2023-07-03T14:57:45Z
• Authors: Michael T. Patterson; Adam L. Burrack; Yingzheng Xu; Grant H. Hickok; Zoe C. Schmiechen; Samuel Becker; Eduardo Cruz-Hino...; Patricia R. Schrank; Ainsley E. Kennedy; Maria M. Firulyova; Ebony A. Miller; Konstantin Zaitsev; Jesse W. Williams; Ingunn M. Stromnes
• Keywords: CD4-Positive T-Lymphocytes; QH301-705.5; Histocompatibility Antigens Class II; CP: Immunology; Article; Monocytes; 3. Good health; Pancreatic Neoplasms; Antigens, Neoplasm; Tumor Microenvironment; Humans; Biology (General); CP: Cancer; Carcinoma, Pancreatic Ductal

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.