miR‐148a‐3p silences the CANX/MHC‐I pathway and impairs CD8+ T cell‐mediated immune attack in colorectal cancer
miR‐148a‐3p silences the CANX/MHC‐I pathway and impairs CD8+ T cell‐mediated immune attack in colorectal cancer
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DOI：
10.1096/fj.202100235r
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发表时间：
2021-08
期刊：
影响因子：
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通讯作者：
Jinxiu Zheng;Ting Yang;Shuhua Gao;M. Cheng;Ying Shao;Y. Xi;Lin-ying Guo;Dong Zhang;
中科院分区：
文献类型：
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作者：
Jinxiu Zheng;Ting Yang;Shuhua Gao;M. Cheng;Ying Shao;Y. Xi;Lin-ying Guo;Dong Zhang;
结直肠癌(CRC)对免疫检查点抑制剂的无反应或获得性抵抗突出了寻找潜在耐受机制的重要性。肿瘤细胞表面主要组织相容性复合体I类分子(MHC-I)的低表达是肿瘤逃避T细胞识别和破坏的主要机制之一。在这项研究中，我们证明了肿瘤中高水平的钙调素(CaNX)与结直肠癌患者的总生存期呈正相关。CanX是一种参与MHC-I分子折叠和组装的伴侣蛋白。利用miRNA靶标预测数据库和荧光素酶分析，我们确定miR-148A-3p是CanX的潜在调节因子。抑制miR-148A-3p可恢复MHC-I的表面水平，并通过促进CaX的表达在体内外显著增强CD8+T细胞介导的免疫攻击的效果。这些结果表明miR-148A-3p可以通过靶向CanX/MHC-I轴在结直肠癌中发挥促癌作用，这为靶向miR-148A-3p/CanX/MHC-I通路治疗结直肠癌提供了理论依据。
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.