T cell exhaustion in cancer is linked to poor clinical outcomes and evidence suggests T cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TILs) and cancer cells for metabolic resources often renders T cells dysfunctional. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TILs. Environmental stress produces epigenome remodeling events within tumor-infiltrating lymphocytes resulting from loss of the histone methyltransferase EZH2. Using a multi-omics approach, we have defined an ARF-mediated, p53-independent mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth. Our data suggest manipulation of T cell EZH2 within the context of cellular therapies may yield lymphocytes which are able to withstand harsh tumor metabolic environments and collateral pharmacologic insults.
|Advisor:||Tackett, Alan J.|
|Commitee:||Raney, Kevin D., Chambers, Timothy C., O'Brien, Charles A., Cannon, Martin J., Opferman, Joseph T., Taverna, Sean D.|
|School:||University of Arkansas for Medical Sciences|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 82/7(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Immunology, Oncology|
|Keywords:||Cancer, Immunotherpay, Lymphocytes, Mtabolism, Proteomics|
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