The Effects of αCTLA-4 Therapy in Combination with a Loss of Function of the Cytosolic Branched-Chain Aminotransferase (BCATc) in T cells Fighting Lymphoma
Description
Neoplastic cells of the lymphoma microenvironment can escape immune surveillance and grow rapidly. One of the features of this plasticity is the release of immunosuppressive signals leading to T cell exhaustion. Exhausted T cells upregulate the CTLA-4 receptor, which dampens the immune response. Use of anti-CTLA-4 (αCTLA-4) antibodies reverses this process, however, αCTLA-4 therapy has limited application and is currently not offered to lymphoma patients. This calls for scientific research in deciphering the molecular barriers that may exist in lymphoma tumors. The cytosolic branched-chain aminotransferase, (BCATc), an enzyme that breaks down leucine, may contribute to the immunosuppressive effect in the lymphoma microenvironment. To understand how BCATc may interfere with αCTLA-4 therapy, mice with BCATc deleted from their T cells (T-BCATcKO) were subjected to 2x10^5 murine EL-4 lymphoma followed by i.p. injection of αCTLA-4, or isotope, on days 2, 5, and 10. Mice were euthanized on day 15 and tumor, draining lymph node, and spleen were collected to analyze T cell populations using a combination of flow cytometry and RT-qPCR. Results showed that T-BCATcKO mice, treated with αCTLA-4 therapy, grew larger tumors than their counterparts. Further analysis revealed a significant increase in intratumoral memory precursor T cells in T-BCATcKO mice undergoing αCTLA-4 therapy. This suggests the deletion of BCATc from T cells, in combination with αCTLA4 therapy, facilitates a switch to memory-like intratumoral environment, which may negatively impact the anti-lymphoma response. Thus, BCATc may be a novel molecular factor to interfere with the response of cancer patients to αCTLA-4 therapy.
Citation Information
Kelm, Tanner and Ananieva-Stoyanova, Elitsa, "The Effects of αCTLA-4 Therapy in Combination with a Loss of Function of the Cytosolic Branched-Chain Aminotransferase (BCATc) in T cells Fighting Lymphoma" (2026). Office of Research DMU Research Symposium. 86.
https://digitalcommons.dmu.edu/researchsymposium/2025rs/2025abstracts/86
The Effects of αCTLA-4 Therapy in Combination with a Loss of Function of the Cytosolic Branched-Chain Aminotransferase (BCATc) in T cells Fighting Lymphoma
Neoplastic cells of the lymphoma microenvironment can escape immune surveillance and grow rapidly. One of the features of this plasticity is the release of immunosuppressive signals leading to T cell exhaustion. Exhausted T cells upregulate the CTLA-4 receptor, which dampens the immune response. Use of anti-CTLA-4 (αCTLA-4) antibodies reverses this process, however, αCTLA-4 therapy has limited application and is currently not offered to lymphoma patients. This calls for scientific research in deciphering the molecular barriers that may exist in lymphoma tumors. The cytosolic branched-chain aminotransferase, (BCATc), an enzyme that breaks down leucine, may contribute to the immunosuppressive effect in the lymphoma microenvironment. To understand how BCATc may interfere with αCTLA-4 therapy, mice with BCATc deleted from their T cells (T-BCATcKO) were subjected to 2x10^5 murine EL-4 lymphoma followed by i.p. injection of αCTLA-4, or isotope, on days 2, 5, and 10. Mice were euthanized on day 15 and tumor, draining lymph node, and spleen were collected to analyze T cell populations using a combination of flow cytometry and RT-qPCR. Results showed that T-BCATcKO mice, treated with αCTLA-4 therapy, grew larger tumors than their counterparts. Further analysis revealed a significant increase in intratumoral memory precursor T cells in T-BCATcKO mice undergoing αCTLA-4 therapy. This suggests the deletion of BCATc from T cells, in combination with αCTLA4 therapy, facilitates a switch to memory-like intratumoral environment, which may negatively impact the anti-lymphoma response. Thus, BCATc may be a novel molecular factor to interfere with the response of cancer patients to αCTLA-4 therapy.
