Turning Cold MPNST Into a Hot Tumor for Immune Checkpoint Blockade Therapy
Abstract
Neurofibromatosis Type 1 (NF1) is one of the most common inherited neurological disorders, affecting about 1 in 3,000 people worldwide. Neurofibromas are hallmark tumors of NF1 that are composed of a mixture of cell types, including Schwann cells, fibroblasts, mast cells, macrophages, and endothelial cells, as well as extracellular materials such as collagen. Most individuals with NF1 will develop cutaneous neurofibromas, benign tumors that arise in the skin and can number from a few to thousands. More than 50% of NF1 individuals will also develop plexiform neurofibroma, a benign tumor that develops along a nerve bundle. However, in about 8-13% of NF1 individuals, the plexiform neurofibroma will transform into a malignant peripheral nerve sheath tumor (MPNST). Complete removal of the tumor(s) with surgery is currently the only available curative treatment for MPNST, but success of the surgery can be limited by large tumor size and/or proximity to complex nerve networks. There is also a high tendency for the tumor to return in these patients (i.e. relapse) following surgery, and metastasis is common. MPNSTs also do not respond to chemotherapy or radiotherapy leading to high mortality. In fact, MPNSTs are the leading cause of death in NF1 patients. Thus, effective treatment strategies for MPNST are desperately needed. NF1 is associated with mutations in the NF1 gene that disrupt the function of the protein it encodes – neurofibromin. Neurofibromin is a RAS GTPase activating protein: it binds to the GTP-bound active form of RAS and enhances its GTPase activity, functioning as an off switch. Inactivating mutations of NF1 result in the activation of multiple effector pathways, including the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. Although inhibition of RAS-activated downstream signaling pathways have been explored as treatments for NF1 and related malignancies, these efforts have not been successful for MPNST, yielding no significant improvement in MPNST patient survival in clinical trials. The use of immune checkpoint blockade (ICB), which reprograms a patient’s immune system to target tumors, has had incredible therapeutic success that has revolutionized treatment strategies for multiple cancer types. However, ICB requires a T cell-rich tumor microenvironment, and, unfortunately, MPNSTs are cold tumors, meaning they lack T cells in the tumor microenvironment. This makes ICB treatment ineffective. Therefore, a strategy to increase T cell density in the tumor microenvironment could enable the use of ICB as a potential therapy for MPNST. The STING protein is involved in innate immunity and plays a critical role in dealing with bacterial and viral DNA infiltration, as well as abnormal self-DNA when found in the cell cytoplasm. Activation of STING has also been shown to enhance antitumor immunity through the induction of secreted pro-inflammatory proteins, including type I interferon (IFN). STING-IFN pathway upregulation increases T cell infiltration into the tumor microenvironment. Consequently, the use of STING agonists (or activators) to elicit immune responses against cancer have been developed and tested in preclinical models and in human patients. In this proposal, we will use small molecule agonists to activate the STING-IFN pathway to boost anti-tumor immunity, creating a T cell–rich MPNST microenvironment. We will then test combining STING activation with ICB as a novel treatment strategy for MPNST. First, we will characterize the MPNST immune microenvironment so that we can compare before and after treatment with STING agonists. Second, we will use STING agonists to reprogram MPNST microenvironment to a T cell-rich one. Finally, we will combine STING-mediated reprogramming of the MPNST immune microenvironment with ICB to establish a new treatment strategy for MPNST. We have expertise in cancer biology and MPNST and are leaders in the NF1 field. This experience, together with th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210356
Entities
People
- Lu Q Le
Organizations
- United States Army
- University of Texas Southwestern Medical Center