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Dissertation/Thesis Abstract

Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Exhaustion
by Koss, Brian Spencer, Ph.D., University of Arkansas for Medical Sciences, 2020, 155; 28262842
Abstract (Summary)

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.

Indexing (document details)
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
Source Type: DISSERTATION
Subjects: Biochemistry, Immunology, Oncology
Keywords: Cancer, Immunotherpay, Lymphocytes, Mtabolism, Proteomics
Publication Number: 28262842
ISBN: 9798557094276
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