The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD‐L1
Abstract Immune checkpoints blockades have shown promising clinical effects in various malignancies, but the overall response rate is low. Here, the immune features are comprehensively characterized in >10 000 cancer patients from The Cancer Genome Atlas and significantly positive correlations ar...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-01-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202001596 |
| _version_ | 1797946758915948544 |
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| author | Hui Li Xinwei Kuang Long Liang Youqiong Ye YongChang Zhang Jialu Li Fangyu Ma Juan Tao Guang Lei Shuang Zhao Juan Su Nong Yang Cong Peng Xiaowei Xu Mien‐Chie Hung Leng Han Hong Liu Jing Liu Xiang Chen |
| author_facet | Hui Li Xinwei Kuang Long Liang Youqiong Ye YongChang Zhang Jialu Li Fangyu Ma Juan Tao Guang Lei Shuang Zhao Juan Su Nong Yang Cong Peng Xiaowei Xu Mien‐Chie Hung Leng Han Hong Liu Jing Liu Xiang Chen |
| author_sort | Hui Li |
| collection | DOAJ |
| description | Abstract Immune checkpoints blockades have shown promising clinical effects in various malignancies, but the overall response rate is low. Here, the immune features are comprehensively characterized in >10 000 cancer patients from The Cancer Genome Atlas and significantly positive correlations are observed between targets of Sunitinib and inhibitory immune checkpoints and suppressive immune cells. It is further confirmed that Sunitinib treatment increases the antitumor immunity in a phase III trial. Mechanistically, it is discovered that Sunitinib regulates the stability of tumor PD‐L1 via p62, that p62 can bind to PD‐L1 and specifically promote its translocation into autophagic lysosome for degradation. Preclinically, Sunitinib shows a synergistic antitumor effect with cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) monoclonal antibody (mAb) in melanoma and nonsmall cell lung cancer (NSCLC) immune competent mice by promoting the tumor‐infiltrating lymphocytes activity. Clinically, a higher PD‐L1 level but a lower p62 level in the tumor region of responders as compared to those of nonresponders among anti‐PD‐1‐treated NSCLC patients is observed. Taken together, by utilizing rigorous computational analysis, functional characterization in vitro and in vivo, and neoadjuvent clinical trial, a novel molecular mechanism is revealed regarding the regulation of PD‐L1 via p62, thus providing a novel therapeutic strategy by the combination treatment of CTLA‐4 with Sunitinib. |
| first_indexed | 2024-04-10T21:16:06Z |
| format | Article |
| id | doaj.art-2daf79e3c38b416287b2de504e27f4a2 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-10T21:16:06Z |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-2daf79e3c38b416287b2de504e27f4a22023-01-20T12:20:39ZengWileyAdvanced Science2198-38442021-01-0182n/an/a10.1002/advs.202001596The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD‐L1Hui Li0Xinwei Kuang1Long Liang2Youqiong Ye3YongChang Zhang4Jialu Li5Fangyu Ma6Juan Tao7Guang Lei8Shuang Zhao9Juan Su10Nong Yang11Cong Peng12Xiaowei Xu13Mien‐Chie Hung14Leng Han15Hong Liu16Jing Liu17Xiang Chen18Department of Dermatology Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Dermatology Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Dermatology Xiangya Hospital Central South University Changsha Hunan 410008 ChinaShanghai Institute of Immunology Department of Immunology and Microbiology Center for Single‐Cell Omics State Key Laboratory of Oncogenes and Related Genes Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaDepartment of Medical Oncology Lung Cancer and Gastrointestinal Unit Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine Central South University Changsha Hunan 410013 ChinaDepartment of Biostatistics HuaJia Biomedical Intelligence ShenZhen 518054 ChinaDepartment of Health Management Center Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Dermatology Affiliated Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 ChinaDepartment of Radiation Oncology Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine Central South University Changsha Hunan 410013 ChinaDepartment of Dermatology Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Dermatology Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Medical Oncology Lung Cancer and Gastrointestinal Unit Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine Central South University Changsha Hunan 410013 ChinaDepartment of Dermatology Xiangya Hospital Central South University Changsha Hunan 410008 ChinaDepartment of Pathology and Laboratory Medicine Perelman School of Medicine 42 University of Pennsylvania Philadelphia PA 19104 USAGraduate Institute of Biomedical Sciences and Center for Molecular Medicine China 44 Medical University Taichung 404 TaiwanDepartment of Biochemistry and Molecular Biology The University of Texas Health Science Center at Houston McGovern Medical School Houston TX 77030 USADepartment of Dermatology Xiangya Hospital Central South University Changsha Hunan 410008 ChinaMolecular Biology Research Center Center for Medical Genetics Hunan Province Key Laboratory of Basic and Applied Hematology School of Life Sciences Central South University Changsha 410078 ChinaDepartment of Dermatology Xiangya Hospital Central South University Changsha Hunan 410008 ChinaAbstract Immune checkpoints blockades have shown promising clinical effects in various malignancies, but the overall response rate is low. Here, the immune features are comprehensively characterized in >10 000 cancer patients from The Cancer Genome Atlas and significantly positive correlations are observed between targets of Sunitinib and inhibitory immune checkpoints and suppressive immune cells. It is further confirmed that Sunitinib treatment increases the antitumor immunity in a phase III trial. Mechanistically, it is discovered that Sunitinib regulates the stability of tumor PD‐L1 via p62, that p62 can bind to PD‐L1 and specifically promote its translocation into autophagic lysosome for degradation. Preclinically, Sunitinib shows a synergistic antitumor effect with cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) monoclonal antibody (mAb) in melanoma and nonsmall cell lung cancer (NSCLC) immune competent mice by promoting the tumor‐infiltrating lymphocytes activity. Clinically, a higher PD‐L1 level but a lower p62 level in the tumor region of responders as compared to those of nonresponders among anti‐PD‐1‐treated NSCLC patients is observed. Taken together, by utilizing rigorous computational analysis, functional characterization in vitro and in vivo, and neoadjuvent clinical trial, a novel molecular mechanism is revealed regarding the regulation of PD‐L1 via p62, thus providing a novel therapeutic strategy by the combination treatment of CTLA‐4 with Sunitinib.https://doi.org/10.1002/advs.202001596immune surveillancep62PD‐L1selective autophagysunitinib |
| spellingShingle | Hui Li Xinwei Kuang Long Liang Youqiong Ye YongChang Zhang Jialu Li Fangyu Ma Juan Tao Guang Lei Shuang Zhao Juan Su Nong Yang Cong Peng Xiaowei Xu Mien‐Chie Hung Leng Han Hong Liu Jing Liu Xiang Chen The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD‐L1 Advanced Science immune surveillance p62 PD‐L1 selective autophagy sunitinib |
| title | The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD‐L1 |
| title_full | The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD‐L1 |
| title_fullStr | The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD‐L1 |
| title_full_unstemmed | The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD‐L1 |
| title_short | The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD‐L1 |
| title_sort | beneficial role of sunitinib in tumor immune surveillance by regulating tumor pd l1 |
| topic | immune surveillance p62 PD‐L1 selective autophagy sunitinib |
| url | https://doi.org/10.1002/advs.202001596 |
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