Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation
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 ti...
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| Language: | English |
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005592.full |
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| author | Ying Zhu Jiao Li Tao Zhang Lei Zhao Min Jin Jinghua Ren Jing Tang Haihong Wang Zhenyu Lin Qing Liang Ruiqi Li Biying Zhang Qingling Hua Guojie Xu Jiayuan Chen Lanqing Wang Dejun Zhang Dandan Yu |
| author_facet | Ying Zhu Jiao Li Tao Zhang Lei Zhao Min Jin Jinghua Ren Jing Tang Haihong Wang Zhenyu Lin Qing Liang Ruiqi Li Biying Zhang Qingling Hua Guojie Xu Jiayuan Chen Lanqing Wang Dejun Zhang Dandan Yu |
| author_sort | Ying Zhu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d793afab723a4d6eb2336efde66c10a4 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d793afab723a4d6eb2336efde66c10a42025-01-29T11:55:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005592Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradationYing Zhu0Jiao Li1Tao Zhang2Lei Zhao3Min Jin4Jinghua Ren5Jing Tang6Haihong Wang7Zhenyu Lin8Qing Liang9Ruiqi Li10Biying Zhang11Qingling Hua12Guojie Xu13Jiayuan Chen14Lanqing Wang15Dejun Zhang16Dandan Yu17Department of Laboratory, People’s Hospital of Yuxi City, Yuxi, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China3 Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China1Shandong Cancer Hospital Affiliated To Shandong First Medical University, Jinan, China1 Department of Pharmacy, Shanghai Fourth People`s Hospital Affiliated to Tongji University, Shanghai, Shanghai, ChinaInstitute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China1 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaInstitute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Emergency, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaBackground 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.https://jitc.bmj.com/content/11/1/e005592.full |
| spellingShingle | Ying Zhu Jiao Li Tao Zhang Lei Zhao Min Jin Jinghua Ren Jing Tang Haihong Wang Zhenyu Lin Qing Liang Ruiqi Li Biying Zhang Qingling Hua Guojie Xu Jiayuan Chen Lanqing Wang Dejun Zhang Dandan Yu Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation Journal for ImmunoTherapy of Cancer |
| title | Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation |
| title_full | Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation |
| title_fullStr | Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation |
| title_full_unstemmed | Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation |
| title_short | Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation |
| title_sort | tumor cemip drives immune evasion of colorectal cancer via mhc i internalization and degradation |
| url | https://jitc.bmj.com/content/11/1/e005592.full |
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