1. Academic Validation
  2. Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation

Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation

  • J Immunother Cancer. 2023 Jan;11(1):e005592. doi: 10.1136/jitc-2022-005592.
Biying Zhang # 1 2 Jiao Li # 1 2 Qingling Hua # 1 2 Haihong Wang 1 Guojie Xu 1 Jiayuan Chen 1 Ying Zhu 1 Ruiqi Li 1 Qing Liang 1 Lanqing Wang 1 Min Jin 1 Jing Tang 1 Zhenyu Lin 1 Lei Zhao 1 Dejun Zhang 1 Dandan Yu 3 Jinghua Ren 3 2 Tao Zhang 3 2
Affiliations

Affiliations

  • 1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China taozhangxh@hust.edu.cn jhrenmed@hust.edu.cn yudandan@hust.edu.cn.
  • # Contributed equally.
Abstract

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.

Keywords

CD8-positive T-lymphocytes; antigen presentation; tumor escape.

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