RT Journal Article
SR Electronic
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
FD BMJ Publishing Group Ltd
SP e005592
DO 10.1136/jitc-2022-005592
VO 11
IS 1
A1 Biying Zhang
A1 Jiao Li
A1 Qingling Hua
A1 Haihong Wang
A1 Guojie Xu
A1 Jiayuan Chen
A1 Ying Zhu
A1 Ruiqi Li
A1 Qing Liang
A1 Lanqing Wang
A1 Min Jin
A1 Jing Tang
A1 Zhenyu Lin
A1 Lei Zhao
A1 Dejun Zhang
A1 Dandan Yu
A1 Jinghua Ren
A1 Tao Zhang
YR 2023
UL http://jitc.bmj.com/content/11/1/e005592.abstract
AB 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.