TY - JOUR
T1 - Vitamin E Enhances Cancer Immunotherapy by Reinvigorating Dendritic Cells via Targeting Checkpoint SHP1
AU - Yuan, Xiangliang
AU - Duan, Yimin
AU - Xiao, Yi
AU - Sun, Kai
AU - Qi, Yutao
AU - Zhang, Yuan
AU - Ahmed, Zamal
AU - Moiani, Davide
AU - Yao, Jun
AU - Li, Hongzhong
AU - Zhang, Lin
AU - Yuzhalin, Arseniy E.
AU - Li, Ping
AU - Zhang, Chenyu
AU - Badu-Nkansah, Akosua
AU - Saito, Yohei
AU - Liu, Xianghua
AU - Kuo, Wen Ling
AU - Ying, Haoqiang
AU - Sun, Shao Cong
AU - Chang, Jenny C.
AU - Tainer, John A.
AU - Yu, Dihua
N1 - Funding Information:
X. Yuan reports a patent for 63/252,721 pending. Y. Duan reports a patent for 63/252.721 pending. Y. Xiao reports a patent for 63/252.721 pending. Y. Qi reports a patent for 63/252.721 pending. A.E. Yuzhalin reports grants from the U.S. Department of Defense outside the submitted work. D. Yu reports grants from the NIH and METAvivor Research and Support, Inc. during the conduct of the study, as well as a patent for 63/252.721 pending. No disclosures were reported by the other authors.
Funding Information:
The single cells from mouse tumor tissues were prepared as described previously (50). The cells were incubated with metal-conjugated Ab cocktails against surface and intracellular proteins (Supplementary Table S9). To analyze the phosphorylated signal proteins, single cells isolated from tumor tissues of EMT6-bearing mice with indicated vehicle or VitE treatment were stimulated by LPS (100 ng/mL) for 15 minutes in vitro and then stained with distinct isotope-labeling phosphorylated Ab cocktails after permea-bilization. Cell samples were then analyzed by Fluidigm Helios Cell Mass Cytometer (RRID:SCR_019917) in the Flow Cytometry and Cellular Imaging Core Facility, which is supported in part by the NIH through MDACC Support Grant (CA016672) and a Shared Instrumentation Award from the Cancer Prevention Research Institution of Texas (CPRIT; RP121010). Detailed CyTOF sample collection and data analysis are described in the Supplementary Methods.
Funding Information:
We thank the NIH Tetramer Core Facility for providing gp70 tetramer and OVA tetramer, Dr. Jedd Wolchok for the B16-GMCSF cell line, Dr. Hideo Yagita for the hybridoma RMP1-14, and Drs. Stephanie Watowich, Chunru Lin, Jianjun Gao, and Florencia McAllister for critical comments on the manuscript. This work was supported by NIH grants R01CA184836 (D. Yu), R01CA208213 (D. Yu), and R01CA231149 (D. Yu), METAVivor research grants #56675 and #58284 (D. Yu), MD Anderson Duncan Family Institute for Cancer Prevention and Risk Assessment (D. Yu), and NIH Cancer Center Support Grant P30CA016672 to MDACC (Flow Cytometry and Cellular Imaging Facility, Functional Genomics Core, Functional Proteomics Core, Research Histology Core, Characterized Cell Line Core, and Research Animal Support Facility-Houston). J.A. Tainer is supported by Cancer Prevention Research Institute of Texas (CPRIT) grant RP180813, NIH grants P01CA092584 and R35CA220430, and the Robert A. Welch Chemistry Chair. D. Yu is the Hubert L. & Olive Stringer Distinguished Chair in Basic Science at MDACC.
Publisher Copyright:
© 2022, American Association for Cancer Research Inc. All rights reserved.
PY - 2022/7/6
Y1 - 2022/7/6
N2 - 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.
AB - 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.
KW - Animals
KW - Cancer Vaccines/therapeutic use
KW - Dendritic Cells
KW - Immunotherapy
KW - Mice
KW - Neoplasms/drug therapy
KW - Protein Tyrosine Phosphatase, Non-Receptor Type 6
KW - Vitamin E/metabolism
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U2 - 10.1158/2159-8290.CD-21-0900
DO - 10.1158/2159-8290.CD-21-0900
M3 - Article
C2 - 35420681
AN - SCOPUS:85134360139
SN - 2159-8274
VL - 12
SP - 1742
EP - 1759
JO - Cancer Discovery
JF - Cancer Discovery
IS - 7
ER -