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 specific metabolites regulate T cell differentiation and function. We have identified alpha-ketoglutarate, a metabolite derived from glutamine, as a regulator in the balance between effector Th1 vs regulatory T cell (Treg) differentiation and ongoing studies are evaluating the impact of myeloablative and non-myeloablative chemotherapy regimens in the metabolic microenvironment. Specifically, alpha-ketoglutarate increases Th1 polarization while significantly inhibiting 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 alpha-ketoglutarate 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 (in collaboration with Drs. David Stroncek and Steven Highfill) and can be predicted through evaluation of antigen-dependent CAR T cell activity. To this end, we are developing systems wherein the dynamic differentiation features of CAR-T cells can be evaluated as a function of the CAR construct and patient-specific characteristics. We are using a high throughput Immunotron system for immune monitoring in collaboration with Gregoire Altan-Bonnet's lab, allowing an analysis of CART as a function of the secretion/consumption of 7 cytokines and T cell activation parameters. This computational pipeline is being used to monitor real-time responses of CAR-T cells from patients who have been treated with CD22-CART and CD19/CD22 CAR vectors, in collaboration with the clinical PI of these trials, Dr. Nirali Shah. These data are being leveraged to optimize CAR manufacturing, evaluate divergent patient outcomes, and enhance durable responses in pediatric leukemia patients.