PROJECT SUMMARY
New immunotherapies targeting lymphomas delivered promising results during recent clinical trials. However,
these therapies were only effective in a small subset of patients with short periods of remission. The results from
these studies suggested the existence of immunosuppression in the tumor microenvironment. Indeed, the
lymphoma microenvironment is a very dynamic network between lymphoma cells and non-malignant
components that may promote tumor growth and consequently drug resistance. Progress in T cell metabolism
has demonstrated that T cells experience a metabolic disadvantage in the tumor microenvironment, which often
manifests in T cell exhaustion that jeopardizes their potential to destroy cancer cells. This reveals a critical need
to explore new (metabolic) approaches to improve T cell performance. Our research team proposes to target the
metabolism of the branched chain amino acids (BCAAs) as a novel metabolic checkpoint of T cell activation in
the lymphoma microenvironment. Our rationale stems from the findings that the BCAA, leucine, is indispensable
for T cells activation, while BCAA metabolism, initiated by the cytosolic (BCATc) and mitochondrial (BCATm)
branched-chain aminotransferases, is a means to direct leucine toward degradation. The objective in this
application is to determine whether a loss of expression of BCATc and BCATm is beneficial for the durability and
functional integrity of T cells during lymphoma eradication in unique pre-clinical mouse models created in our
laboratory. The long-term goal of this application is to provide new means to improve the T cell-mediated immune
response and to address the challenges with T cell-driven anti-lymphoma immunotherapy. The central
hypothesis is that BCATc, supported by BCATm, serves to provide checkpoint control on T cell function by being
a part of a negative feedback loop regulation of T cell activation. Deletion of the BCAT genes from T cells,
individually or in combination, may provide a metabolic advantage of T cells allowing them to remain activated
and to successfully combat lymphoma growth. To test the central hypothesis, we identified three specific aims:
(1) Investigate how the expression of BCATc and BCATm changes upon T cell subset differentiation and whether
the BCAT proteins are essential for T cell lineage commitment and function, (2) Determine whether a blockage
in the transamination of BCAAs enhances the T cell response to lymphoma tumors, and (3) Investigate whether
a loss of expression of BCATc in mouse T cells can overcome the lymphoma resistance to anti-CTLA4 therapy.
Completion of this project will not only provide the opportunity to improve the current treatment options for
lymphoma patients but will also engage students in pre-clinical cancer studies. The students will highly benefit
from acquiring hands-on research experience in cancer, which can be translated into enhanced research skills,
scientific reasoning, and better understanding of treatment approaches.
