TY - JOUR T1 - Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2022-005592 VL - 11 IS - 1 SP - e005592 AU - Biying Zhang AU - Jiao Li AU - Qingling Hua AU - Haihong Wang AU - Guojie Xu AU - Jiayuan Chen AU - Ying Zhu AU - Ruiqi Li AU - Qing Liang AU - Lanqing Wang AU - Min Jin AU - Jing Tang AU - Zhenyu Lin AU - Lei Zhao AU - Dejun Zhang AU - Dandan Yu AU - Jinghua Ren AU - Tao Zhang Y1 - 2023/01/01 UR - http://jitc.bmj.com/content/11/1/e005592.abstract N2 - Background Loss of major histocompatibility complex class I (MHC-I) in tumor cells limits the use of immune checkpoint blockade (ICB) in colorectal cancer. Nevertheless, the regulatory mechanism of MHC-I downregulation in tumor cells has not been fully elucidated. Overexpression of CEMIP in tumor tissues is associated with a poor prognosis in colorectal cancer. Here, in this research, we aim to address the role of CEMIP in mediating MHC-I expression in tumor cells and investigate the underlying regulatory mechanisms.Method Protein levels were analyzed by western blotting. Flow cytometry analysis was used to examine immune cells. Protein–protein interactions were investigated by co-immunoprecipitation and proximity ligation assays. The intracellular trafficking of MHC-I was revealed by an immunofluorescent technique. In addition, the effect of CEMIP on tumor growth and the antitumor efficacy of targeting CEMIP in combination with ICB therapy were evaluated in murine models of colorectal cancer.Results We reported that CEMIP specifically downregulated the expression of MHC-I on the surface of murine and human colon cancer cells, hindering the cytotoxicity of CD8+ T cells. We also demonstrated that CEMIP restricted CD8+ T-cell antitumor activities both in vitro and in vivo due to impaired MHC-I-mediated antigen presentation. Correspondingly, the combination of CEMIP inhibition and ICB impeded tumor growth and enhanced therapeutic efficacy. Mechanistically, CEMIP acted as an adaptor for the interaction betweenMHC-I and clathrin, which drove MHC-I internalization via clathrin-dependent endocytosis. Furthermore, CEMIP anchored internalized MHC-I to lysosomes for degradation, disrupting the recycling of MHC-I to the cell surface.Conclusion Overall, our study unveils a novel regulatory mechanism of MHC-I on tumor cell surfaces by CEMIP-mediated internalization and degradation. Furthermore, targeting CEMIP provides an effective strategy for colorectal cancer immunotherapy.All data relevant to the study are included in the article or uploaded as supplementary information. ER -