Metabolic regulation of T cell effector function and anti-tumor immunotherapy

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

One critical aspect impacting on T cell proliferation and function is the host environment. The activation and effector functions of adoptively-transferred T lymphocytes are associated with increased energetic and biosynthetic demands, generally secured by augmented nutrient entry and utilization. However, the potential of an engineered anti-tumor T cell (using a chimeric antigen receptor (CAR) or T cell receptor (TCR)) to respond to tumor antigens is often negatively modulated by the metabolic environment of the tumor. This environment is conditioned by nutrient composition, waste products, oxygen concentration, pH and physical forces, amongst others. The dysregulated growth of cancer cells can directly influence the extracellular environment and negatively impact on the ensuing immune response. These differences in metabolite environment may account for at least one of the mechanisms modulating the success of CAR-T cells directed against diffuse leukemias (i.e. CD19-CAR) as compared to solid tumors. Indeed, we have found that the differential use of glutamine and glucose regulates T cell differentiation and function. Remarkably, glutamine deprivation causes naive CD4+ T cells to differentiate into suppressor regulatory T cells, even under Th1 polarizing conditions while high Glut1 levels promote effector cytokine secretion. Indeed, we have identified alpha-ketoglutarate, a metabolite derived from glutamine, as a regulator in the balance between Th1 vs Treg differentiation and ongoing studies are evaluating the impact of myeloablative and non-myeloablative chemotherapy regimens in the metabolic microenvironment. Furthermore, we have found that alpha-ketoglutarate increases Th1 polarization while significantly inhibiting regulatory T cell (Treg) generation. Consistent with these data, alpha-ketoglutarate promoted the effector profile of Treg-polarized CAR T cells against a tumor antigen. Mechanistically, we determined that this metabolite alters membrane fluidity and induces a robust lipidome-wide remodelling. The impact of this remodelling on anti-tumor function will be evaluated. Furthermore, we hypothesize that variability in CAR T cell immunotherapeutic potential is affected by variations in manufacturing platforms and can be predicted through evaluation of antigen-dependent CAR T cell activity. To this end, it is critical to develop systems wherein the dynamic differentiation features of CAR-T cells can be evaluated as a function of the CAR construct and patient-specific characteristics. To this end, our group is collaborating with Nirali Shah and Gregoire Altan-Bonnet (NCI) to develop an experimental and computational pipeline to monitor real-time responses of CAR-T cells in response to the specific leukemia antigen. High throughput analyses of these parameters, utilizing samples from patients who have been treated with CD22-CART and CD19/CD22 CAR vectors at the NCI and Stanford sites, are being leveraged to optimize CAR manufacturing, evaluate divergent patient outcomes, and enhance durable responses in pediatric leukemia patients.