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  5. Congratulations Dr. Koss!

Congratulations Dr. Koss!

Congratulations to Brian Koss who successfully defended his Ph.D. dissertation entitled “Epigenetic control of Cdkn2a.Arf protects tumor-infiltrating lymphocytes from exhaustion” on November 18th. Brian was a student in the laboratory of Dr. Alan Tackett and is now a post-doctoral fellow in the Center for Translational Pediatric Research as part of the Proteomics Technology Development Shared Resource under the direction of Dr. Rick Edmondson. A summary of his research is below.

 

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.

Posted by Chris Lesher on November 23, 2020

Filed Under: Department News

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