Journal
ONCOIMMUNOLOGY
Volume 5, Issue 9, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2016.1211219
Keywords
Colon cancer; macrophage polarization; miR-155; STAT1; Tim-3
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Funding
- National 973 Fund, China [2013CB530506, 2015CB553704]
- National Natural Sciences Foundation of China [81471540, 81471529, 81472647]
- Key program of the Beijing Natural Sciences Foundation [7141007]
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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.
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