Mouse EL4 lymphoma strains differentially respond to a loss of BCATc from T cells and αCTLA4 immunotherapy

Introduction/Rationale: Lymphoma tumors can escape immune surveillance and grow rapidly. One of the features of this plasticity is immunosuppressive signals causing T cell exhaustion. Exhausted T cells upregulate the CTLA4 receptor, which dampens the immune response. Use of αCTLA4 reverses this process, however, αCTLA4 therapy has limited application and is currently not offered to lymphoma patients. This calls for research into deciphering the molecular barriers in lymphoma tumors. The cytosolic branched-chain aminotransferase (BCATc), an enzyme that breaks down leucine, may contribute to immunosuppression within the lymphoma microenvironment.

Methods: To understand how BCATc influences the efficacy of αCTLA4 therapy, T-BCATcfl/fl mice and mice with a loss of BCATc from T cells (T-BCATcKO) were subcutaneously injected with 2x10^5 of low (EL4) and high (EL4OVA) immunogenic lymphoma and randomly assigned 10 μg/gram body weight i.p. injections of IgG isotype or αCTLA4 on days 2, 5 and 10-post lymphoma challenge. Mice were euthanized on day 15 and T cell populations in tumors and draining lymph nodes were analyzed by flow cytometry.

Results: Prior to αCTLA4 therapy, T-BCATcKO mice responded to EL4 and EL4OVA lymphoma with a significant 40-50 % delay in tumor development. This was further reduced when T-BCATcKO mice were subjected to αCTLA4 following inoculation with EL4OVA lymphoma. 78 % of these mice showed a 5-fold reduction in tumor masses compared to mice injected with isotope antibody. In contrast, only 12.5 % of T-BCATcKO mice carrying EL4 tumors responded with reduced tumor volumes to αCTLA4; the rest of the mice developed ~40 % larger tumors with significantly reduced percentage of memory precursor CD4+ T cells compared to T-BCATcKO mice injected with IgG, or T-BCATcfl/fl mice treated with αCTLA4.

Conclusion: These findings stress the differential response of low and high immunogenic lymphomas to BCATc expression and may have clinical implication in targeting BCATc for combinatorial immune therapies in humans.