Metabolic reprogramming is a fundamental process underlying the growth of cancer cells and activated lymphocytes. These rapidly dividing cells markedly upregulate aerobic glycolysis (Warburg metabolism) and also reprogram mitochondrial oxidative phosphorylation (OXPHOS) to support the energy and growth demands. Moreover, mTOR signaling is a central regulator of anabolic metabolism in cancer cells and lymphocytes. While Warburg and mitochondrial metabolism and mTOR signaling are being actively studied, we are just beginning to appreciate the involvement of other biosynthetic programs such as de novo lipid synthesis (lipogenesis). Emerging evidence highlights that cancer immunotherapy is a powerful tool to combat cancers, but immune tolerance mediated by immunosuppressive regulatory T cells (Tregs) represents a major obstacle for effective anti-tumor immunity. Although mTOR was generally considered a crucial negative regulator of Tregs, our genetic studies have revealed that mTORC1 is a pivotal positive determinant of Treg function by linking immune signals to the lipogenic program. In our preliminary studies, disruption of the lipogenic program in Tregs rendered the mice to reject tumor cells but did not cause obvious autoimmune disorders under steady state. We hypothesize that lipogenic program contributes to Treg suppressive activity in the tumor microenvironment, which could represent a novel target for cancer immunotherapy. We will test this hypothesis by establishing the roles of Treg lipogenic programs in tumor immunity, and determining the metabolic and signaling basis whereby lipogenesis programs Treg functions. We predict these studies will establish a new paradigm on our understanding of lipogenic program in Tregs and how this impinges upon tumor immunity. Insights gained from this project will likely lead to innovative strategies on cancer immunotherapy by capitalizing on metabolic reprogramming of Tregs.

Public Health Relevance

Statement Regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance, but also represent a major hurdle for effective immune responses toward cancer. Tregs depend on the metabolic pathways mediated by mTOR signaling and lipid biosynthesis to execute these functions, and modulation of these processes exerts a strong effect on cancer immunity. Therefore, a better understanding of the metabolic pathways in Tregs is essential for our efforts to prevent and treat cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA221290-02
Application #
9527109
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mccarthy, Susan A
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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