Decoding brain cancer through the lens of metabolism and immunology.
The overall goals of our research are to understand the complexity of brain cancer, characterize the mechanisms driving its heterogeneity and explore new treatment strategies leading to translational therapeutic development. Our laboratory has specific interests in tumor metabolism, tumor immunology, cell-cell communications and its role in driving disease presentation.
- Metabolic interactions between tumor cells and the immune system in GBM: A potential Achilles heel of GBM for novel therapeutics: The glioma microenvironment is very complex and heterogeneous, a feature that impedes both the understanding of their biology as well as the elaboration of efficient clinical interventions. The focus of our proposal is to mechanistically understand the nature of the communications that take place in the tumor microenvironment, especially between immune suppressive cells and tumor cells that resist therapy but also to test the therapeutic effect of disrupting these interactions to treat brain tumors. The long-term goal of this project is to translate the information gained into strategies useful as clinical therapies improving disease outcome.
- Slow cycling cell RNA-based T cell therapy to prevent recurrence in GBM: The severity of glioblastoma is due to pathogenic drivers that are tolerant to conventional therapies. We have discovered a specific pool of slow-cycling cells showing greater treatment resistance and tumorigenicity. We propose to leverage our ability to purify these cells to develop a novel targeted immunotherapy strategy based on the use of immunogenic antigens isolated from these clinically relevant population of cells as activator of immune effectors in the context of adoptive cell therapy to prevent recurrence in GBM.
- Potentiating T cell anti-tumor efficiency via metabolic reprogramming for adoptive cellular immunotherapy to treat brain cancer: GBM are a challenge for neuro-oncologists and current therapies are minimally effective. Standard-of-care treatment is almost inevitably followed by disease recurrence. Adoptive T cell transfer has emerged as a viable therapeutic for brain malignancies. While promising, the efficacy of this approach is often limited by a complex immunosuppressive tumor microenvironment. These complexities mean that more sophisticated T cell products are required. T cells undergo metabolic reprogramming upon activation marked by an increased glucose uptake. This project proposes to test a new approach based on reprograming the metabolic qualities of anti-tumor immune cells to enhance immunotherapy for the treatment of GBM. We hypothesize that brain tumor cells outcompete host or adoptively transferred T cells for metabolic substrates like glucose, directly limiting their function and supporting tumor progression. This project examines the effect of enhancing T cell glucose metabolism through genetic manipulation, in vitro metabolic conditioning in mouse models of GBM and using patient-based platforms.
- Co-opting TME lactate signal to benefit T cell therapy: Complex alterations of energy pathways have been described in cancers and originate from the Warburg hypothesis, which postulates that the majority of cancer cells derive their energy from aerobic glycolysis. This specific metabolic reprogramming of strong engagement in the glycolytic pathway is a hallmark of glioblastoma (GBM). As part of their high glycolytic rate, GBM secrete metabolic byproducts such as lactate, which acts as an important oncometabolite and immunosuppressor. Capitalizing on our current knowledge of tumor metabolism and how metabolic pathways affect immune response, the goal of this project is to test an innovative therapeutic modality based on reprograming the metabolic qualities of anti-tumor immune cells to enhance immunotherapy for the treatment of GBM. We hypothesize that co-opting lactate signal may be a useful approach to overcome metabolically driven tumor-imposed immunosuppression and for developing efficient immunotherapies. This project investigates the efficacy of lactate receptor genetic engineering in T cells in the context of adoptive cell therapy to treat GBM.