Cancer affects people of all ages, but the risk of developing most forms of this disease increases with age. How the immune system changes with age and the effect that this has on the development or control of cancer is not completely clear. However we do know that, in general, CD8 T cells play a crucial role in immunity to cancer. Upon activation, CD8 T cells undergo a predictable developmental program characterized by distinct phases encompassing first the expansion, and then contraction, of Ag-specific effector (TE) populations, followed by the persistence of long-lived memory cells (TM). Since long-lived CD8 TM cells mediate protective immunity to the re-establishment of cancer, the mechanisms underlying the generation and maintenance of these cells remain a highly desirable target for clinical intervention. Our previous work has revealed that the promotion of mitochondrial fatty acid oxidation (FAO), a pathway of lipid catabolism that fuels the TCA cycle, in CD8 T cells during an immune response is crucial to their development into long-lived TM cells. We found that the mammalian target of rapamycin (mTOR) plays a central role in this process and exploited this finding to enhance CD8 TM development after vaccination. This proposal extends our novel concept that cellular metabolism regulates the development of CD8 TM and that the mTOR pathway modulates this process. Based on our observations, and a panel of supportive preliminary data, we hypothesize that 1) inhibitors of mTOR promote the development of CD8 TM cells that protect against cancer, and 2) mTOR controls this process by regulating metabolism in these cells. The long-term goal of these studies is to facilitate the development of immunotherapies against cancer.

Public Health Relevance

Our proposal extends our recent novel findings demonstrating that cellular metabolism regulates the development of immunological memory; and that the mTOR pathway modulates this process. We will establish how mTOR regulates metabolism in immune cells and determine whether mTOR inhibitors; which have traditionally been used to treat cancer for their direct anti-tumor properties; can actually promote tumor-specific immunological memory and thereby protect against cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Wu, Duojiao; Sanin, David E; Everts, Bart et al. (2016) Type 1 Interferons Induce Changes in Core Metabolism that Are Critical for Immune Function. Immunity 44:1325-36
Huang, Stanley Ching-Cheng; Everts, Bart; Ivanova, Yulia et al. (2014) Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 15:846-55
Amiel, Eyal; Everts, Bart; Fritz, Daniel et al. (2014) Mechanistic target of rapamycin inhibition extends cellular lifespan in dendritic cells by preserving mitochondrial function. J Immunol 193:2821-30
Everts, Bart; Amiel, Eyal; Huang, Stanley Ching-Cheng et al. (2014) TLR-driven early glycolytic reprogramming via the kinases TBK1-IKK? supports the anabolic demands of dendritic cell activation. Nat Immunol 15:323-32
O'Sullivan, David; van der Windt, Gerritje J W; Huang, Stanley Ching-Cheng et al. (2014) Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41:75-88
Pearce, Erika L; Poffenberger, Maya C; Chang, Chih-Hao et al. (2013) Fueling immunity: insights into metabolism and lymphocyte function. Science 342:1242454
Chang, Chih-Hao; Curtis, Jonathan D; Maggi Jr, Leonard B et al. (2013) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153:1239-51
Pearce, Erika L; Pearce, Edward J (2013) Metabolic pathways in immune cell activation and quiescence. Immunity 38:633-43
van der Windt, Gerritje J W; Pearce, Erika L (2012) Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev 249:27-42
Amiel, Eyal; Everts, Bart; Freitas, Tori C et al. (2012) Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. J Immunol 189:2151-8

Showing the most recent 10 out of 11 publications