Targeting Protein Phosphatase 2A (PP2A) to Overcome Macrophage-Mediated Immunosuppression in Glioblastoma
Abstract
Glioblastoma (GBM) is one the most aggressive cancers, with median survival of less than 15 months and 5-year survival of 4.1%. Current therapies, consisting of chemotherapy, surgery, and radiation therapy offer little benefit but carry significant side effects. New treatment for GBM is therefore critically needed. A form of immunotherapy, named checkpoint therapy (ICT), aims to boost one’s immune cells, T-cells, to attack cancer. ICT has made remarkable improvement in the treatment of some advanced cancers including melanoma and lung cancer. However, trials of ICT in GBM patients have failed so far. It is critical to understand why GBM does not respond to ICT and to develop new ways to overcome this resistance. Our group was first to identify a new target, Protein Phosphatase 2A (PP2A), to boost immune cell activity against cancer by blocking PP2A function with an inhibitor LB-100. PP2A functions in both cancer and immune cells. Combining LB-100 with ICT can cure ~25% of GBM tumors in mice. However, it is unclear how PP2A inhibition increases effectiveness of ICT in GBM. This proposal aims to understand how inhibiting PP2A can boast immune system against brain tumor and therefore help to bring this treatment to the clinic and help patients with GBM. Compared to other cancers, GBM tissues has many macrophages, a heterogeneous group of immune cells that can kill tumors or make tumors grow faster by suppressing T-cells that recognize and kill tumor cells. In GBM, most of the macrophages are “bad” immune cells that suppress the “good” T cells. Therefore, even with ICT, the energized T cells still cannot overcome suppression by macrophages. However, a district group of macrophages is able to help the “good” T cells to kill cancer cells and they exist in low frequency within GBM. Based on some recent evidence from studying virus infection in macrophages, we believe that inhibiting PP2A in macrophages turn them into cells that help T cells battle GBM. This discovery will introduce a new strategy to fight GBM and may benefit many patients with this horrible disease. Career Development: My long-term research goal is to understand how brain tumors avoid the attack of immune cells and in doing so develop new therapy to boost the immune system’s ability to fight against tumor. Support from this Career Development Award will enable me to gain additional expertise, receive mentorship, strengthen collaborations, and obtain resources to conduct research that will ultimately benefit patient care. This award will not only allow me to continue my work on studying PP2A as a novel target for immunotherapy, but also broaden my scope of research to study macrophages, an important subset of immune cells that mediate the suppression of T cells in brain tumor. I will be collaborating some of the world’s leading experts in the macrophage biology. I believe that this award will further my professional development on multiple levels and is necessary to achieve my research and career goals. Application of the research: Completion of this project will clarify the function of PP2A in immune cells within brain tumor that could potentially be the key to overcome GBM resistance to ICT. I plan to work with collaborators at the National Cancer Institutes and LIVESTRONG cancer institutes at the University of Texas Austin to initiate clinical trials combining ICT and PP2A inhibitors. In addition, this study will provide important information about different populations of macrophages in GBM that will inform future studies to discover new treatment of GBM. Military Relevance: Brain cancer is the leading cause of cancer-related deaths in patients younger than 35, which account for nearly 90% of active enlisted military members. In addition, military personnel with exposure to ionizing radiation, such as nuclear weapons technicians and dental technicians, are at increased risk for developing GBM. Finally, data suggest that veterans with GBM has a signific
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010428
Entities
People
- Rongze Lu
Organizations
- United States Army
- University of Texas at Austin