The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD-L1

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

doi:10.1002/advs.202001596

The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD-L1

Adv Sci (Weinh). 2020 Nov 27;8(2):2001596. doi: 10.1002/advs.202001596. eCollection 2021 Jan.

Authors

Hui Li^{1

2

3}, Xinwei Kuang^{1

4

5

6}, Long Liang^{1

2}, Youqiong Ye^{7

8}, YongChang Zhang⁹, Jialu Li¹⁰, Fangyu Ma¹¹, Juan Tao¹², Guang Lei¹³, Shuang Zhao^{1

4

5

6}, Juan Su^{1

4

5

6}, Nong Yang⁹, Cong Peng^{1

4

5

6}, Xiaowei Xu¹⁴, Mien-Chie Hung^{15

16}, Leng Han⁸, Hong Liu^{1

17

4

5

6}, Jing Liu², Xiang Chen^{1

4

5

6}

Affiliations

¹ Department of Dermatology Xiangya Hospital Central South University Changsha Hunan 410008 China.
² Molecular 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 China.
³ Molecular Science and Biomedicine Laboratory State Key Laboratory for Chemo/Biosensing and Chemometrics College of Biology College of Chemistry and Chemical Engineering Collaborative Innovation Center for Chemistry and Molecular Medicine Hunan University Changsha Hunan 410082 China.
⁴ Hunan Key Laboratory of Skin Cancer and Psoriasis Changsha Hunan 410008 China.
⁵ Hunan Engineering Research Center of Skin Health and Disease Changsha Hunan 410008 China.
⁶ Xiangya Clinical Research Center for Cancer Immunotherapy Central South University Changsha Hunan 410008 China.
⁷ Shanghai 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 China.
⁸ Department of Biochemistry and Molecular Biology The University of Texas Health Science Center at Houston McGovern Medical School Houston TX 77030 USA.
⁹ Department 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 China.
¹⁰ Department of Biostatistics HuaJia Biomedical Intelligence ShenZhen 518054 China.
¹¹ Department of Health Management Center Xiangya Hospital Central South University Changsha Hunan 410008 China.
¹² Department of Dermatology Affiliated Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China.
¹³ Department of Radiation Oncology Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine Central South University Changsha Hunan 410013 China.
¹⁴ Department of Pathology and Laboratory Medicine Perelman School of Medicine 42 University of Pennsylvania Philadelphia PA 19104 USA.
¹⁵ Graduate Institute of Biomedical Sciences and Center for Molecular Medicine China 44 Medical University Taichung 404 Taiwan.
¹⁶ Department of Biotechnology Asia University Taichung 413 Taiwan.
¹⁷ Research Center of Molecular Metabolomics Xiangya Hospital Central South University Changsha Hunan 410008 China.

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.

Keywords: PD‐L1; immune surveillance; p62; selective autophagy; sunitinib.