Abstract 5147: Mice with T cells deficient in the Cytosolic Branched Chain Aminotransferase reduce the tumor burden of low and high immunogenic strains of Lymphoma
Authors: Figueroa Lucas D. , Wetzel Tanner , Wheeler Leighton , Adam Christie , Boyer Michael , Ananieva Elitsa 
Published: April 2023

Current immunotherapies rely on modulating host immunity to induce an anti-tumor immune response. The efficacy of such a response depends on the immunogenicity of the tumor, which varies greatly between different cancers or the same cancer in different individuals. While most lymphomas are immunogenic, non-malignant T cells that infiltrate the lymphoma microenvironment are subjected to immunosuppressive signals and areas of nutrient depletion, which leads to T cell exhaustion and inhibition of T cell function. Metabolic enzymes, such as the cytosolic branched chain aminotransferase, BCATc, exert immunosuppressive effects limiting T cells ability to function. Previous research described BCATc as a negative regulator of T cell activation, thus identifying BCATc as a potential target for immunotherapeutic modulation in the tumor microenvironment (TME).

In the current study we exploit a low (EL4) and high (EL4-OVA) immunogenic murine lymphoma strains to explore how a loss of BCATc in T cells impacts their ability to produce anti-lymphoma immunity in mice. We used 12 week old male mice with BCATc deleted from T cells (T-BCATcKO) and control T-BCATcfl/fl mice that express the transgenic floxed version of BCATc. Mice were injected with 2.5x105 cells belonging to the low (EL4) or high (EL4-OVA) immunogenic strains and tumor growth, body weight, and food intake were monitored for up to 15 days followed by collection of tumor tissues and organs. Tumors were then lysed, and the protein profile of each tumor was determined by monitoring changes in expression of protein markers of T cell exhaustion (TOX, CD39), apoptosis (BAX, PUMA), or signaling proteins, such as the ribosomal S6 protein, the protein kinase B (AKT), and the energy sensor the AMP-activated protein kinase (AMPK).

T-BCATcKO mice showed significant reduction in tumor growth compared to control mice regardless of the lymphoma strain being tested. The mouse cohort with the biggest number of tumor free mice was the T-BCATcKO cohort injected with EL4 cells (13% of the mice were tumor free on day 9). However, EL4-OVA cells grew into smaller tumors across all cohorts. Mice had comparable food intake but T-BCATcKO mice, injected with EL4 cells, had a significantly lower body weight. In T-BCATcKO mice, the reduced EL4 tumor mass correlated with upregulated AMPK and AKT along with higher expression of PUMA. The reduced EL4-OVA tumor masses correlated with downregulated S6 and decreased TOX expression, but high expression of BAX compared to the corresponding tumors isolated from T-BCATcfl/fl mice. These findings suggest that T cells deficient in BCATc can reduce lymphoma growth regardless of the immunogenicity of the lymphoma stain likely by establishing catabolic state and inducing apoptosis. Thus, BCATc may play an immunosuppressive role in the lymphoma TME and the absence of BCATc from T cells may help T cells combat lymphoma.

Citation Format: Lucas D. Figueroa, Tanner Wetzel, Leighton Wheeler, Christie Adam, Michael Boyer, Elitsa Ananieva. Mice with T cells deficient in the Cytosolic Branched Chain Aminotransferase reduce the tumor burden of low and high immunogenic strains of Lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5147.