During a productive immune response na?ve tumor antigen-specific T cells will become activated and produce a variety of effector molecules that mediate tumor clearance. However, T cells often experience a progressive decline in function and responsiveness during cancer, and without properly functioning T cells, tumors will continue to grow. This T cell dysfunction, or exhaustion, is thought to result from continuous exposure to antigen, such that repetitive stimulation drives T cells into deeper states of unresponsiveness where functions such as proliferation, cytokine production, cytotoxic ability, and finally survival are lost. Many cancer treatments currently under development attempt to target pathways in T cells that will pull them back from their dysfunctional state and boost effector functions. While therapies using this approach hold promise, the underlying basis of why T cells become exhausted and/or dysfunctional during cancer is not completely understood and a clear understanding of this process is a critical barrier that must be overcome in order to effectively design new anti-cancer treatments. This proposal addresses this issue. It is based on our novel finding that in T cells metabolism posttranscriptionally regulates effector function and that this process is controlled by competition from other cells for nutrients in a given microenvironment. We found that the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), by engaging or disengaging the glycolysis pathway, regulates the posttranscriptional production of cytokines by T cells. We showed that activated T cells can use either oxidative phosphorylation (OXPHOS) or glycolysis to support proliferation and survival, but when T cells switch between these ATP generating programs, as can occur with changes in nutrient availability, or co-stimulatory or growth factor signals, GAPDH switches from its function as a metabolic enzyme in glycolysis to its function as an RNA binding protein controlling expression of immunomodulatory factors. Thus while OXPHOS can support T cell survival and proliferation, only glycolysis can facilitate full effector status. These findings showed that glucose (Glc) availability directly determines whether a T cell can produce cytokines after the receipt of activation signals. Given that many tumors also engage glycolysis (Warburg effect) we hypothesize that tumor-infiltrating T cells that experience a loss of function during cancer may do so as a result of tumor-imposed Glc restrictions. To test this we have used in vitro approaches and an in vivo sarcoma model and our preliminary data support that tumors impose Glc restrictions on T cells that dampens the T cell's ability to engage glycolysis and produce effector cytokines. Our experiments will establish whether the tumor microenvironment is nutrient-restrictive for tumor-infiltrating T cells, and whether the inability of T cells to engage glycolysis renders them unable to produce cytokines (via posttranscriptional mechanisms) and control tumor growth. We hope that by completing our aims we will provide crucial knowledge toward developing new treatments to reverse immune dysfunction in cancer through the manipulation of metabolic pathways.

Public Health Relevance

The adaptive immune response is critical for surviving infection and cancer. However, all too often during cancer, cells in the adaptive immune system experience a progressive decline in function and responsiveness and fail to clear or control tumors. Building from our strong preliminary data this proposal sets out to establish the link between cellular metabolism and its regulation of immune cell function, with a view to understanding how this is influenced by the tumor microenvironment. With the completion of our aims we hope to provide crucial knowledge toward developing promising new treatments to reverse immune dysfunction in cancer through the manipulation of metabolic pathways.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Howcroft, Thomas K
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Washington University
Schools of Medicine
Saint Louis
United States
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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
Chang, Chih-Hao; Pearce, Erika L (2016) Emerging concepts of T cell metabolism as a target of immunotherapy. Nat Immunol 17:364-8
van der Windt, Gerritje J W; Chang, Chih-Hao; Pearce, Erika L (2016) Measuring Bioenergetics in T Cells Using a Seahorse Extracellular Flux Analyzer. Curr Protoc Immunol 113:3.16B.1-3.16B.14
Kaiko, Gerard E; Ryu, Stacy H; Koues, Olivia I et al. (2016) The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites. Cell 165:1708-20
Buck, Michael D; O'Sullivan, David; Klein Geltink, Ramon I et al. (2016) Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming. Cell 166:63-76
Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure et al. (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17:656-65
Chang, Chih-Hao; Qiu, Jing; O'Sullivan, David et al. (2015) Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell 162:1229-41
O'Sullivan, David; Pearce, Erika L (2015) Targeting T cell metabolism for therapy. Trends Immunol 36:71-80
Buck, Michael D; O'Sullivan, David; Pearce, Erika L (2015) T cell metabolism drives immunity. J Exp Med 212:1345-60
Pearce, Erika L; Poffenberger, Maya C; Chang, Chih-Hao et al. (2013) Fueling immunity: insights into metabolism and lymphocyte function. Science 342:1242454

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