November 23, 2020

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.