Abstract 1807: T cell conditional knockout mouse model of the mitochondrial branched chain aminotransferase (BCATm) responds with delayed tumor growth to a lymphoma challenge

Abstract

Abstract Enzymes in amino acid catabolism are emerging as attractive targets for cancer therapies. The mitochondrial branched-chain amino transferase (BCATm), an enzyme catalyzing the first step in leucine, valine, and isoleucine degradation, has been recently implicated in cancer growth but its role in T cell driven anti-cancer immunity has never been explored. To fulfill the gap in current scientific knowledge and address some of the challenges with lymphoma immunotherapies, we used the CD4-Cre-Lox recombination to create a conditional knockout mouse (T-BCATmKO) with CD4+ and CD8+ T cells deficient in the Bcat2 gene that encodes BCATm. Based on initial studies showing that a deletion of BCATm from T cells leads to increased glycolytic and oxygen metabolism and up-regulation of complex 1 of the mammalian target of rapamycin (mTORC1) signaling, we hypothesized that if BCATm is absent from T cells, this would stimulate T cell activation leading to improved T cell function in mice challenged with lymphoma. For this purpose, T-BCATmKO and T-BCATmfl/fl male mice (15-16 weeks old) were subcutaneously injected with 2.5x105 mouse lymphoma EG7-OVA cells. Tumor growth, animal weight, and food intake were recorded daily for a period of 20 days. Mice developed tumors around day 10 and this was not associated with weight loss or poor feeding of the mice as no changes in body weights or food intake between the different mouse groups were observed. Statistical analysis via one-way ANOVA revealed that T-BCATmKO mice had significantly delayed tumor growth compared to T-BCATmfl/fl mice (P= 0.05). In addition, CD4+ T cells isolated from T-BCATmKO mice released significantly more IFNγ after 48-72 hours of activation suggesting that CD4+ T cells from T-BCATmKO mice were more active than T cells from T-BCATmfl/fl mice. This study revealed that targeting BCATm in T cells may offer an advantage in mice to better fight lymphoma cancer and represents an attractive target for future immunotherapeutic anti-cancer approaches. Citation Format: Christie Adam, Alexander Martin, Rebekah Betar, Mercedes Foster, Michael Boyer, Elitsa Ananieva. T cell conditional knockout mouse model of the mitochondrial branched chain aminotransferase (BCATm) responds with delayed tumor growth to a lymphoma challenge [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1807.