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

被引:12
|
作者
Patterson, Michael T. [1 ,2 ]
Burrack, Adam L. [1 ,3 ]
Xu, Yingzheng [1 ,2 ]
Hickok, Grant H. [1 ,3 ]
Schmiechen, Zoe C. [1 ,3 ]
Becker, Samuel [1 ,3 ]
Cruz-Hinojoza, Eduardo [1 ,3 ]
Schrank, Patricia R. [1 ,2 ]
Kennedy, Ainsley E. [1 ,2 ]
Firulyova, Maria M. [4 ,5 ]
Miller, Ebony A. [1 ,3 ]
Zaitsev, Konstantin [4 ]
Williams, Jesse W. [1 ,2 ]
Stromnes, Ingunn M. [1 ,3 ,6 ,7 ]
机构
[1] Univ Minnesota, Ctr Immunol, Minneapolis, MN 55414 USA
[2] Univ Minnesota, Dept Integrat Biol & Physiol, Minneapolis, MN 55414 USA
[3] Univ Minnesota, Dept Microbiol & Immunol, Minneapolis, MN 55414 USA
[4] ITMO Univ, Comp Technol Lab, St Petersburg, Russia
[5] Natl Med Res Ctr, St Petersburg, Russia
[6] Univ Minnesota, Masonic Canc Ctr, Med Sch, Minneapolis, MN 55414 USA
[7] Univ Minnesota, Ctr Genome Engn, Med Sch, Minneapolis, MN 55414 USA
来源
CELL REPORTS | 2023年 / 42卷 / 07期
关键词
INFILTRATING MACROPHAGES; CANCER; EXPRESSION; DYNAMICS; PROMOTES; IMMUNITY; SUBSETS; GAMMA; MICROENVIRONMENT; IMMUNOTHERAPY;
D O I
10.1016/j.celrep.2023.112732
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 IFNg 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.
引用
收藏
页数:23
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