Differential impact of BCATc inhibition on T cell exhaustion in mice challenged with lymphoma and subjected to anti-CTLA4 therapy
Description
A major barrier in cancer immunotherapy is T-cell exhaustion, resulting from prolonged T-cell activation during tumor destruction. The branched-chain aminotransferase (BCATc) is overexpressed in tumors supporting tumor proliferation and metabolic adaptation. Anti-CTLA4 therapy is an anti-tumor drug preventing deactivation of T-cells by blocking the CTLA4 receptor. Exhausted T-cells cannot be rescued by anti-CTLA4 therapy. While it is not fully understood how BCATc impacts T-cell exhaustion, we hypothesized that a loss of BCATc correlates with an increased state of T-cell exhaustion in spleens of mice challenged with lymphoma and subjected to anti-CTLA4 therapy. Male mice with a BCATc gene knockout in T- cells (T-BCATcKO mice) and control littermates were inoculated with 2.5 × 10⁵ murine EL4-lymophma cells followed by i.p. injection of anti-CTLA4, or an isotope, on days 2, 5, and 10. Spleens were collected of day 15 followed by western blot assay to determine changes in the protein expression of T-cell exhaustion markers: TOX, TIGIT, CD244, CD39, and LAG3. In the isotope group, splenocytes of T-BCATcKO mice showed a decreased expression of TOX, LAG3, and TIGIT compared to control mice. In the T-BCATcKO experimental group, the expression of TOX and TIGIT were significantly increased in response to the anti-CTLA4 therapy. These findings suggest that a combination between a loss of BCATc from T-cells and anti-CTLA4 therapy may contribute to T-cell exhaustion. However, a loss of BCATc from T-cells, alone, may be beneficial for reduced T-cell exhaustion, aiding in prolonged life of T-cells and their ability to combat cancer.
Citation Information
Fagan, Madison; Wetzel, Tanner; Kelm, Tanner; Kotula, Anna; and Ananieva-Stoyanova, Elitsa, "Differential impact of BCATc inhibition on T cell exhaustion in mice challenged with lymphoma and subjected to anti-CTLA4 therapy" (2026). Office of Research DMU Research Symposium. 80.
https://digitalcommons.dmu.edu/researchsymposium/2025rs/2025abstracts/80
Differential impact of BCATc inhibition on T cell exhaustion in mice challenged with lymphoma and subjected to anti-CTLA4 therapy
A major barrier in cancer immunotherapy is T-cell exhaustion, resulting from prolonged T-cell activation during tumor destruction. The branched-chain aminotransferase (BCATc) is overexpressed in tumors supporting tumor proliferation and metabolic adaptation. Anti-CTLA4 therapy is an anti-tumor drug preventing deactivation of T-cells by blocking the CTLA4 receptor. Exhausted T-cells cannot be rescued by anti-CTLA4 therapy. While it is not fully understood how BCATc impacts T-cell exhaustion, we hypothesized that a loss of BCATc correlates with an increased state of T-cell exhaustion in spleens of mice challenged with lymphoma and subjected to anti-CTLA4 therapy. Male mice with a BCATc gene knockout in T- cells (T-BCATcKO mice) and control littermates were inoculated with 2.5 × 10⁵ murine EL4-lymophma cells followed by i.p. injection of anti-CTLA4, or an isotope, on days 2, 5, and 10. Spleens were collected of day 15 followed by western blot assay to determine changes in the protein expression of T-cell exhaustion markers: TOX, TIGIT, CD244, CD39, and LAG3. In the isotope group, splenocytes of T-BCATcKO mice showed a decreased expression of TOX, LAG3, and TIGIT compared to control mice. In the T-BCATcKO experimental group, the expression of TOX and TIGIT were significantly increased in response to the anti-CTLA4 therapy. These findings suggest that a combination between a loss of BCATc from T-cells and anti-CTLA4 therapy may contribute to T-cell exhaustion. However, a loss of BCATc from T-cells, alone, may be beneficial for reduced T-cell exhaustion, aiding in prolonged life of T-cells and their ability to combat cancer.
