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

Authors

Xiangliang Yuan
Yimin Duan
Yi Xiao
Kai Sun
Yutao Qi
Yuan Zhang
Zamal Ahmed
Davide Moiani
Jun Yao
Hongzhong Li
Lin Zhang
Arseniy E Yuzhalin
Ping Li
Chenyu Zhang
Akosua Badu-Nkansah
Yohei Saito
Xianghua Liu
Wen-Ling Kuo
Haoqiang Ying
Shao-Cong Sun
Jenny C Chang
John A Tainer
Dihua Yu

Publication Date

7-6-2022

Journal

Cancer Discovery

Abstract

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.

Significance: 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.

Keywords

Animals, Cancer Vaccines, Dendritic Cells, Immunotherapy, Mice, Neoplasms, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Vitamin E

DOI

10.1158/2159-8290.CD-21-0900

PMID

35420681

PMCID

PMC9262841

PubMedCentral® Posted Date

1-6-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes