Targeting a Protumorigenic Immunosuppressive Loop in MPNST
Abstract
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas arising from the myelinating nerve sheath. These tumors occur in 8-13% of patients with Neurofibromatosis Type 1, a tumor predisposition syndrome caused by germline mutations in neurofibromin (NF1). The 5-year survival rate for MPNSTs is less than 50%, and new treatment options are desperately needed. The NF1+/- microenvironment alters the tumor immune landscape, and immunosuppressive cells are abundant in NF1 patient tumors. Thus, new therapeutic strategies that target immunosuppressive cells are critical to improving outcomes in MPNST. However, there remains a critical gap in our understanding of immune cell function in MPNSTs. Mast cells are immunosuppressive cells that contribute to neurofibroma development, although their role in MPNST is not well understood. We have used sophisticated mouse models to determine that mast cells are key drivers of MPNST growth. Strong preclinical data shows that elimination of mast cells in established MPNSTs can slow tumor growth, suggesting these cells are attractive therapeutic targets. We have also identified an immunosuppressive loop between Nf1+/- mast cells, T cells, and tumor cells that we predict drives MPNST pathogenesis. Our main objective is to define events driving immunosuppression in MPNSTs, with an emphasis on translational approaches that will improve treatment response for Neurofibromatosis patients. In this proposal, we will test the hypothesis that a pro-tumorigenic, immunosuppressive loop is regulating mast cell dynamics to support MPNST growth. This study will fill a critical gap in our understanding of immune cell networks in MPNSTs and potentially determine new therapeutic targets in the Nf1+/- tumor microenvironment. This proposal will use innovative CRISPR/Cas9 technology that allows us to understand the mechanistic complexity of Nf1+/- immune cells in MPNST biology in ways that would be impossible with traditional mouse modeling approaches. We will use these approaches to test therapeutic targeting of immunosuppressive mechanisms in preclinical models. If successful, this proposal will identify specific molecular targets in the immune system that will slow the growth of MPNSTs. There is strong clinical rationale for targeting immunosuppressive cells in MPNSTs, since this strategy can improve response to conventional chemotherapies and checkpoint blockade immunotherapies in other cancers. Our collaborative team of clinicians and basic scientists is well positioned to rapidly translate these findings into the clinic, if successful. Since all of these therapeutic approaches are currently available for clinical use, clinical trials for MPNST patients could begin within 3-4 years. In summary, this proposed research will benefit NF1 patients by improving our understanding of key immune cell networks in MPNST biology and validating new therapeutic targets that can improve patient care and outcomes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110348
Entities
People
- Rebecca D Dodd
Organizations
- United States Army
- University of Iowa