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Latest News
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.
A full list of collaborating authors and their disclosures can be found with the full paper here.
The University of Texas MD Anderson Cancer Center applauds the unanimous vote by Houston City Council today to amend the city’s ordinance against smoking in public places to include e-cigarettes. Using any form of e-cigarette in public places is now prohibited in the City of Houston.
“Today’s actions represent an important step to reduce secondhand smoke exposure of any type for all Houstonians,” said Ernest Hawk, M.D., vice president and division head of Cancer Prevention and Population Sciences. “We support the City of Houston’s recognition of vaping as a public health concern, especially for youth and young adults, who are most vulnerable to nicotine addiction.”
Through the collaborative efforts of MD Anderson’s EndTobacco® program, the Governmental Relations team and the Cancer Prevention and Population Sciences division, MD Anderson experts have served as educational resources on this issue for the Houston Health Department and city council members.
More than 2 million young adults were estimated to use e-cigarettes in 2021. In Texas, one in four teens has tried e-cigarettes. E-cigarettes have not been proven to be safer than cigarettes and most contain nicotine and other chemicals. Some studies suggest that young people who use e-cigarettes may go on to use traditional tobacco products, which are responsible for up to 30% of all cancer-related deaths and 20% of all deaths in the United States.
E-cigarettes have also not been proven as a smoking cessation tool and are not approved by the Food and Drug Administration for this purpose. MD Anderson has multiple resources available to help teens and adults learn about the dangers of vaping and to begin their quit journey, including:
- This is Quitting: a free and anonymous text message quit program for Texans aged 13-24, offered by the Truth Initiative® with MD Anderson. Text VAPEFREETX to 88709 to join.
- Cessation studies: free research studies available for adults in Texas at any stage of smoking cessation. Visit smokefreestudy.org to learn more.
- Community programs: free presentations to educate children and adults about the dangers of smoking and tobacco use. Visit mdanderson.org/community to learn more.
Researchers at The University of Texas MD Anderson Cancer Center have discovered that two distinct classes of cancer-associated fibroblasts (CAFs) accumulate in the pancreatic tumor microenvironment and play opposing roles to promote and restrain pancreatic cancer development.
The preclinical findings suggest that appropriately targeting these unique CAF populations may offer strategies to improve the use of other treatments, such as chemotherapy and immunotherapy. The results were published today in Cancer Discovery, a journal of the American Association for Cancer Research.
“Cancer-associated fibroblasts are known to regulate cancer progression, but targeting these cells in pancreatic cancer has largely failed to improve patient outcomes and has, in some cases, worsened response,” said lead author Kathleen McAndrews, Ph.D., postdoctoral fellow in Cancer Biology. “Our findings provide the first evidence of the functional heterogeneity of CAFs in pancreatic cancer that may explain the variations in patient outcomes.”
Fibroblasts, a type of cell found in connective tissue, are involved in important biological processes, such as wound repair. Cancer-associated fibroblasts are those that accumulate in tumors. These cells can be found in large numbers in pancreatic cancers, but their precise role in cancer development had remained unclear.
The researchers performed single-cell RNA sequencing to analyze gene expression and clarify the types of CAFs present in pancreatic tumors. They identified two distinct subsets of CAFs marked by expression of fibroblast activation protein (FAP) and alpha-smooth muscle actin (αSMA).
Interestingly, the researchers found that expression of these proteins in treatment-naïve human tumor samples correlated with eventual outcomes. Increased expression of αSMA was associated with significantly improved overall survival (OS), whereas elevated FAP levels were associated with significantly decreased OS.
Using novel mouse models, the researchers demonstrated that FAP+ and αSMA+ CAFs play distinct and opposing roles in the tumor microenvironment. Loss of FAP+ cells suppressed tumor progression and improved OS, suggesting these cells act to promote tumor development.
Conversely, loss of αSMA+ fibroblasts resulted in more aggressive tumors and shorter OS, indicating that these cells work to block pancreatic cancer progression.
Loss of FAP+ vs. αSMA+ cells resulted in distinct gene expression changes in the tumor, resulting in altered regulation of various cancer-associated pathways and different accumulation of immune cells in the tumor microenvironment.
To clarify the distinct roles of FAP+ and αSMA+ cells, the research team also analyzed secreted proteins that may affect the tumor and surrounding cells. The immune signaling protein interleukin 6 (IL-6) is produced by both classes of CAFs. Loss of IL-6 in αSMA+ cells, but not FAP+ cells, improved responses to chemotherapy and immunotherapy with significantly improved OS.
These results are indicative of the complex and heterogeneous roles of these different classes of CAFs, explained senior author Raghu Kalluri, M.D., Ph.D., professor and chair of Cancer Biology.
“This is a new discovery that helps move the field forward, with a new appreciation of the biology of pancreatic cancer and possible strategies for therapeutic interventions,” Kalluri said. “Our next steps are to identify therapies that can target the tumor promoting fibroblasts while sparing the sum beneficial responses of our body in its effort to fight cancer.”
McAndrews led the study together with Yang Chen, Ph.D., and J. Kebbeh Darpolor, Ph.D. A full list of collaborating authors and their disclosures can be found with the paper here.
This research was supported primarily by the Cancer Prevention and Research Institute of Texas (CPRIT) (RP150231) with additional funding from the National Institutes of Health/National Cancer Institute (UL1TR000371, P01CA117969, P30CA016672), the Sid W. Richardson Foundation, the American Legion Auxiliary Fellowship and Ergon Foundation Postdoctoral Fellowships.