title: Tim-3 promotes tumor-promoting M2 macrophage polarization by binding to STAT1 and suppressing the STAT1-miR-155 signaling axis.
abstract: T cell Ig mucin-3 (Tim-3), an immune checkpoint inhibitor, shows therapeutic potential. However, the molecular mechanism by which Tim-3 regulates immune responses remains to be determined. In particular, very little is known about how Tim-3 works in innate immune cells. Here, we demonstrated that Tim-3 is involved in the development of tumor-promoting M2 macrophages in colon cancer. Manipulation of the Tim-3 pathway significantly affected the polarization status of intestinal macrophages and the progression of colon cancer. The Tim-3 signaling pathway in macrophages was explored using microarray, co-immunoprecipitation, gene mutation, and high-content analysis. For the first time, we demonstrated that Tim-3 polarizes macrophages by directly binding to STAT1 via residue Y256 and Y263 in its intracellular tail and inhibiting the STAT1-miR-155-SOCS1 signaling axis. We also identified a new signaling adaptor of Tim-3 in macrophages, and, by modulating the Tim-3 pathway, demonstrated the feasibility of altering macrophage polarization as a potential tool for treating this kind of disease.
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, China; Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Xingwei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Respiratory Diseases, First Affiliated Hospital of the Chinese PLA General Hospital , Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: The Population and Family Planning Cadres College of Henan Province , Zhengzhou, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: Shuaijie
authors.initials: S
authors.lastname: Dou
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: Guojiang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: Renxi
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: He
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Hou
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, China; The Population and Family Planning Cadres College of Henan Province, Zhengzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: Jiannan
authors.initials: J
authors.lastname: Feng
authors.affiliation: Institute of Immunology, Medical School of Henan University , Kaifeng, China.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences , Beijing, China.
authors.forename: Gencheng
authors.initials: G
authors.lastname: Han
keywords: Colon cancer; STAT1; Tim-3; macrophage polarization; miR-155