Vitamin E can boost immunotherapy responses by reinvigorating dendritic
cells

Date:
April 14, 2022
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
Using retrospective clinical data and in-depth lab studies,
researchers have discovered that vitamin E can enhance immunotherapy
responses by stimulating dendritic cells in the tumor.



FULL STORY ========================================================================== Combining a retrospective analysis of clinical records with in-depth
laboratory studies, researchers at The University of Texas MD Anderson
Cancer Center have discovered that vitamin E can enhance immunotherapy responses by stimulating the activity of dendritic cells in the tumor. The findings were published today in Cancer Discovery.


==========================================================================
The researchers demonstrated that vitamin E directly binds and blocks
the activity of the SHP1 checkpoint protein in dendritic cells, which
increases antigen presentation and primes T cells for an anti-tumor immune response. The results point to possible new therapeutic approaches to
improve immunotherapy outcomes, including combinations with vitamin E
as well as directly targeting SHP1 in dendritic cells.

"This study broadens our understanding of factors that can influence
responses to immunotherapies," said corresponding author Dihua Yu, M.D.,
Ph.D., chair ad interim of Molecular & Cellular Oncology. "We demonstrated
that vitamin E can reinvigorate dendritic cell antigen presentation via
the inhibition of SHP1.

These results indicate that vitamin E-treated or SHP1-silenced dendritic
cells and dendritic cell-derived extracellular vesicles could be developed
as potent immunotherapies for future clinical applications." Vitamin E connected with improved immunotherapy responses Immune checkpoint
inhibitors, a type of immunotherapy, provide long-lasting responses
for many patients with cancer, but not all benefit. There is a need
to understand these varied responses in order to improve outcomes for
more patients.

Dietary supplements are thought to boost immunity, but little is known
about the effects of supplements on immunotherapy activity. To explore
the connection, the researchers performed a retrospective analysis of
clinical data from MD Anderson patients treated with immunotherapy.



========================================================================== Patients with melanoma who took vitamin E while on anti-PD-1/PD-L1
checkpoint inhibitors had significantly improved survival compared to
patients who didn't take vitamin E or multivitamins. This finding was replicated in an independent mixed cohort of patients with breast,
colon and kidney cancers. However, patients taking vitamin E while
being treated with chemotherapy did not experience the same benefits, suggesting the effects were unique to chemotherapy.

Next, the researchers demonstrated that vitamin E enhanced responses
to checkpoint inhibitors in immunogenic mouse models of breast cancer
and melanoma. However, models with low levels of tumor-infiltrating
dendritic cells did not benefit from vitamin E, suggesting the effects
were dependent on these cells.

Deciphering the effects of vitamin E on dendritic cells Dendritic cells
are a specific class of immune cells responsible for presenting abnormal proteins -- called antigens -- to prime T cells, which is an essential
step in the anti-tumor immune response. However, tumor-associated
dendritic cells can become dysfunctional due to suppressive signals in
the tumor microenvironment.

The researchers demonstrated that the vitamin E treatment led
to upregulation of several activation markers on the dendritic
cells. Additionally, dendritic cells from tumors treated with vitamin
E promoted more T cell proliferation relative to controls, suggesting
vitamin E enhanced the priming step.



========================================================================== Through molecular and structural studies, the researchers discovered
that vitamin E enters dendritic cells and binds to the SHP1 protein --
which acts as a checkpoint to regulate dendritic cell activity -- to block
its activity and enhance dendritic cells' functionality to prime T cells.

Blocking SHP1 genetically mimicked the results with vitamin E, leading
to increased antigen presentation that stimulated T cell anti-tumor
responses.

Similarly, blocking SHP1 enhanced antigen presentation in extracellular vesicles released by dendritic cells -- another important mode of
communication between dendritic cells and T cells.

Targeting SHP1 may be a novel therapeutic strategy As vitamin E appears
to improve the antigen presentation of dendritic cells, the researchers investigated whether vitamin E could enhance responses from therapies
known to release tumor antigens and recruit dendritic cell infiltration.

Laboratory findings demonstrated that vitamin E treatment could
augment the effects of cancer vaccines and immunogenic chemotherapies
combined with checkpoint inhibitors, including in a model of immunotherapy-resistant pancreatic cancer.

"SHP1 is an attractive target to effectively activate dendritic cells
for the development of potent immunotherapy," said lead author Xiangliang
Yuan, Ph.D., research scientist in Molecular & Cellular Oncology. "This
work yielded important insights on the interaction between vitamin
E and SHP1 that will guide us to develop more specific allosteric
SHP1 inhibitors. Compellingly, it appears that unleashing dendritic
cells by inhibiting SHP1 may be an advantageous strategy to enhance
antitumor immunity." The research team is now exploring opportunities
with clinical collaborators at MD Anderson to prospectively evaluate
the effects of vitamin E in combination with checkpoint inhibitors and
other immunotherapies. Team members also are exploring opportunities to
develop a targeted SHP1 inhibitor as well as SHP1- modified dendritic
cells and dendritic cell-derived extracellular vesicles as novel future therapeutic options.

This research was supported by the National Institutes of Health
(R01CA184836, R01CA208213, R01CA231149, P30CA016672, P01CA092584,
R35CA220430), METAVivor (56675, 58284), the MD Anderson Duncan Family
Institute for Cancer Prevention and Risk Assessment, the Cancer Prevention
and Research Institute of Texas (CPRIT) (RP180813), the Robert A. Welch
Chair in Chemistry, and the Hubert L. & Olive Stringer Distinguished
Chair in Basic Science.


========================================================================== Story Source: Materials provided by University_of_Texas_M._D._Anderson_Cancer_Center. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. 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. Vitamin E Enhances
Cancer Immunotherapy by Reinvigorating Dendritic Cells via
Targeting Checkpoint SHP1. Cancer Discovery, 2022; DOI:
10.1158/2159-8290.CD-21-0900 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220414110858.htm

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