miR-148a-3p silences the CANX/MHC-I pathway and impairs CD8+ T cell-mediated immune attack in colorectal cancer.

Abstract

Nonresponse, or acquired resistance to immune checkpoint inhibitors in colorectal cancer (CRC) highlight the importance of finding potential tolerance mechanisms. Low expression of major histocompatibility complex, class I (MHC-I) on the cell surface of the tumor is one of the main mechanisms of tumor escape from T-cell recognition and destruction. In this study, we demonstrated that a high level of calnexin (CANX) in the tumors is positively correlated with the overall survival in colorectal cancer patients. CANX is a chaperone protein involved in the folding and assembly of MHC-I molecules. Using miRNA target prediction databases and luciferase assays, we identified miR-148a-3p as a potential regulator of CANX. Inhibition of miR-148a-3p restores surface levels of MHC-I and significantly enhanced the effects of CD8+ T-cell-mediated immune attack in vitro and in vivo by promoting CANX expression. These results reveal that miR-148a-3p can function as a tumor promotor in CRC by targeting the CANX/MHC-I axis, which provides a rationale for immunotherapy through targeting the miR-148a-3p/CANX/MHC-I pathway in patients with CRC.

• Authors: Jinxiu Zheng, Ting Yang, Shuhua Gao, Minrong Cheng, Ying Shao, Yanfeng Xi, Linzhi Guo, Dong Zhang, Wei Gao, Guozhen Zhang, Lijun Yang, Tao Yang
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 35 Issue 8 Pg. e21776 (08 2021) ISSN: 1530-6860 [Electronic] United States
• PMID: 34324740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Federation of American Societies for Experimental Biology.

Chemical References

• CANX protein, human
• Histocompatibility Antigens Class II
• MIRN148 microRNA, human
• MicroRNAs
• Calnexin

Topics

• Animals
• CD8-Positive T-Lymphocytes (physiology)
• Calnexin (genetics, metabolism)
• Cell Line, Tumor
• Colorectal Neoplasms (immunology, therapy)
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Histocompatibility Antigens Class II (genetics, metabolism)
• Humans
• Mice
• MicroRNAs (genetics, metabolism)
• Neoplasms, Experimental (therapy)