Vitamin E Enhances Cancer Immunotherapy by Reinvigorating Dendritic Cells via Targeting Checkpoint SHP1

• Published in: Cancer discovery Vol. 12; no. 7; pp. 1742 - 1759
• Main Authors: Yuan, Xiangliang, Duan, Yimin, Xiao, Yi, Sun, Kai, Qi, Yutao, Zhang, Yuan, Ahmed, Zamal, Moiani, Davide, Yao, Jun, Li, Hongzhong, Zhang, Lin, Yuzhalin, Arseniy E., Li, Ping, Zhang, Chenyu, Badu-Nkansah, Akosua, Saito, Yohei, Liu, Xianghua, Kuo, Wen-Ling, Ying, Haoqiang, Sun, Shao-Cong, Chang, Jenny C., Tainer, John A., Yu, Dihua
• Format: Journal Article
• Language: English
• Published: United States 06.07.2022
• Subjects: Animals; Cancer Vaccines - therapeutic use; Dendritic Cells; Immunotherapy; Mice; Neoplasms - drug therapy; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Vitamin E - metabolism
• ISSN: 2159-8274; 2159-8290; 2159-8290
• DOI: 10.1158/2159-8290.CD-21-0900

Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune-checkpoint therapy (ICT), are unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated patients with cancer who took vitamin E (VitE) had significantly improved survival. In mouse models, VitE increased ICT antitumor efficacy, which depended on dendritic cells (DC). VitE entered DCs via the SCARB1 receptor and restored tumor-associated DC functionality by directly binding to and inhibiting protein tyrosine phosphatase SHP1, a DC-intrinsic checkpoint. SHP1 inhibition, genetically or by VitE treatment, enhanced tumor antigen cross-presentation by DCs and DC-derived extracellular vesicles (DC-EV), triggering systemic antigen-specific T-cell antitumor immunity. Combining VitE with DC-recruiting cancer vaccines or immunogenic chemotherapies greatly boosted ICT efficacy in animals. Therefore, combining VitE supplement or SHP1-inhibited DCs/DC-EVs with DC-enrichment therapies could substantially augment T-cell antitumor immunity and enhance the efficacy of cancer immunotherapies. The impacts of nutritional supplements on responses to immunotherapies remain unexplored. Our study revealed that dietary vitamin E binds to and inhibits DC checkpoint SHP1 to increase antigen presentation, prime antitumor T-cell immunity, and enhance immunotherapy efficacy. VitE-treated or SHP1-silenced DCs/DC-EVs could be developed as potent immunotherapies. This article is highlighted in the In This Issue feature, p. 1599.