Date of Award

Spring 5-15-2017

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells in the tumor microenvironment, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, and thereby allowing tumor progression. We demonstrate that enhancing glycolysis in an antigenic ‘regressor’ tumor is sufficient to override the ability of T cells to respond to a major tumor rejection antigen, allowing progression of tumors that are normally rejected. Checkpoint blockade therapy is used clinically to promote immune rejection of progressing tumors. We show that checkpoint blockade (anti-CTLA-4, anti-PD-1, and anti-PD-L1) monoclonal antibodies (mAbs) restore glucose in the microenvironment of progressing tumors, permitting T cell glycolysis and IFN-γ production. Furthermore, we unexpectedly found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes. These data reflect a novel role for PD-L1 in tumor glucose utilization. Together our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer and suggest that checkpoint blockade therapy may be targeting this mechanism. Glucose has been viewed as a major carbon source for adenosine triphosphate (ATP) generation, which is not only essential for the maintenance of cellular bioenergetics, but also critical for the regulation of effector T cell function. Consistent with the model that glucose consumption by antigenic tumors can metabolically restrict infiltrating T cells (TILs) and directly dampen their cytokine production, leading to tumor progression, it is conceivable that supplementation of glucose may rescue T cell hyporesponsiveness as a result of nutrient depletion. However, resupplying TILs with glucose ex vivo does not fully restore cytokine production, indicating that mechanisms beyond substrate limitation contribute to loss of effector functions in TILs. Exactly how T cells reprogram their metabolism in a nutrient restricted microenvironment and how this influences their effector functions remains unclear. In the second part of this study, we focus on understanding the metabolic alteration of T cells experiencing long-term glucose restriction. We found that T cells deprived of glucose lose responsiveness to exogenous glucose over time. Their inability to acquire glucose and thus engage glycolysis contributes to a hyporesponsive state characterized by impaired cytokine production. However, glucose restricted T cells remain responsive to acetate, which is the substrate for acetyl coenzyme A (acetyl-CoA) synthesis and thus is positioned at the intersection of metabolism and genetic regulation. The rescue of effector cytokine production of T cells by acetate supplementation was dependent on the nuclear-cytoplasmic acetylCoA synthetase enzyme (ACSS2). Our results demonstrate an alternative metabolic pathway engaged by T cells in a dearth of glucose. Combining therapies that blunt tumor metabolism with those that promote glycolysis in T cells or distinct metabolic pathway triggered by alternative metabolites that directly regulate cytokine gene expression may generate more effective T cell based immunotherapies in the context of human disease including cancer

Language

English (en)

Chair and Committee

Erika L. Pearce & Paul M. Allen

Committee Members

Marco Colona, Brian T. Edelson, Chyi-Song Hsieh, Gene Oltz,

Comments

Permanent URL: https://doi.org/10.7936/K7W957M8

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