BCAT1 targeted metabolic reprogramming in myeloid derived suppressor cells in glioblastoma

About This Grant

Project Summary/Abstract This proposal encompasses a research and training plan that will transition Dr. Jackson from a mentored role to an independent investigator. She is an Assistant Professor of Neurosurgery at the University of Pennsylvania with a background in brain tumor immunobiology. Her long-term goal is to become an independently funded neurosurgeon-scientist with a translational laboratory focused on understanding the immunobiology and immunometabolism of brain tumors to develop novel immune-based therapies against these tumors. Her short- term goals, that will be facilitated through the K08, include gaining technical proficiency in measuring metabolites and metabolic flux in immune cell using mass spectrometry and stable isotope tracing. Furthermore, she aims to develop expertise in advanced gene knockout methods and sophisticated conditional knockout mouse models for preclinical therapeutic testing, with the ultimate aim of translating her findings into clinically relevant trials. Dr. Jackson has chosen Dr. Celeste Simon as her primary mentor and Dr. John Wherry as her co-mentor. Dr. Simon is a renowned expert in cancer and immune cell metabolism and Dr. Wherry is a world leader in T cell biology including the mechanism of T cell exhaustion and immunotherapy resistance. In addition, she has assembled a strong and complementary scientific advisory committee composed of basic scientists and physician-scientists from diverse and complementary fields to support her in her research direction and career development. Dr. Jackson's recent manuscript in Science identified myeloid-derived suppressor cell (MDSC) populations that are unique to glioblastoma (GBM) that drive tumor aggression through immune suppression and direct promotion of tumor growth. Gene and protein expression analyses demonstrated that the most induced cellular programs in MDSCs are dominated by metabolic pathways. Yet it remains unclear the mechanisms of how metabolic processes regulate MDSC functionality. The proposed research focuses on identifying how metabolic reprogramming in these cells drive their function, specifically the role of branched-chain amino acid (BCAA) metabolism. Dr. Jackson hypothesizes that BCAT1, the first enzyme in BCAA metabolism drives metabolic reprogramming of MDSCs to contribute to their function. Thus, she will test whether 1) BCAT1 regulates MDSC differentiation or immunosuppressive function (Aim 1), and 2) BCAT1 in MDSC facilitates their ability to promote GBM tumor growth (Aim 2). Dr. Jackson will leverage her unique role as a neurosurgeon-scientist and the robust research support at University of Pennsylvania to provide valuable insights into these questions. These studies will advance the field of GBM immunotherapy by elucidating the role of BCAA metabolism and BCAT1 in regulating the function of MDSCs. These results will lead to innovative therapeutics targeting the myeloid compartment of GBM microenvironments that can be complimentary and synergistic with immune checkpoint inhibitors. The mentorship and training provided will effectively transition Dr. Jackson to an independent research career leveraging immunometabolism to develop novel immune-based therapies against these tumors.