| Autor: |
Brian, Koss, Bradley D, Shields, Erin M, Taylor, Aaron J, Storey, Stephanie D, Byrum, Allen J, Gies, Charity L, Washam, Samrat Roy, Choudhury, Jeong, Hyun Ahn, Hidetaka, Uryu, Jason B, Williams, Kimberly J, Krager, Tung-Chin, Chiang, Samuel G, Mackintosh, Rick D, Edmondson, Nukhet, Aykin-Burns, Thomas F, Gajewski, Gang Greg, Wang, Alan J, Tackett |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Cancer Res |
| ISSN: |
1538-7445 |
| Popis: |
T cell exhaustion in cancer is linked to poor clinical outcomes, where evidence suggests T cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Environmental stress produces epigenome remodeling events within TIL resulting from loss of the histone methyltransferase EZH2. Here we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TIL. A multi-comics approach revealed a Cdkn2a.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 in vitro and in vivo. Our data suggest that manipulation of T cell EZH2 within the context of cellular therapies may yield lymphocytes that are able to withstand harsh tumor metabolic environments and collateral pharmacologic insults. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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