Immune-Schwann Cell Signaling in Neurofibroma Development
Abstract
Inflammation, presence of immune cells, and high levels of molecules causing inflammation called cytokines are characteristics of neurofibromas and have been shown to contribute to the development of this disease. Activation and traffic of immune cells to the site of inflammation/infection is driven by cytokines. Our laboratory has recently shown that a population of immune cells, namely T-cells and dendritic cells, which are known to have the ability to recognize and fight off infectious agents/pathogens effectively and optimally, are present in neurofibromas. We have also shown that they participate in promoting neurofibroma by communicating with the Schwann cells bearing Nf1 mutation that secrete/produce inflammatory cytokines. It is unclear, however, what triggers cytokine production/secretion in Schwann cells and the subsequent immune cell infiltration. I propose that the STING pathway, a mechanism known to be activated upon sensing fragments of DNA caused by DNA damage, is involved in the production/secretion of inflammatory cytokines in neurofibroma. This is then followed by infiltration of T-cells and dendritic cells, which then causes inflammation and neurofibroma formation. To test this, I will define when the STING pathway is activated after Nf1 loss in Schwann cells. Then I will investigate the impact of the STING signaling in the production/secretion of cytokines in Nf1 mutant Schwann cells by genetic manipulation and pharmacological intervention. Last, I will test whether inhibiting the STING pathway in our neurofibroma animal model will prevent neurofibroma development. It is anticipated that this project will potentially uncover a preclinical application that will benefit neurofibroma patients. The overall outcomes and significance of this project are two-way. First, there is insufficient evidence to show the therapeutic potential of immunotherapy in neurofibroma. This project will potentially be the first to provide novel therapeutic targets that are involved in modulating the immune landscape in neurofibroma; this will open an avenue to the potential use of immunotherapeutic agents by targeting the STING axis that may improve neurofibroma patient outcomes. It is noteworthy that, despite the success of MEK inhibitor in shrinking neurofibroma, its effect is temporary and a subset of patients respond poorly. Therefore other targets, such as the STING pathway being investigated in this proposal, may offer an alternative therapy for neurofibroma in NF1 patients, and targeting the STING pathway may augment conventional therapy to robustly prevent neurofibroma growth and development. Another significant outcome resulting from this project may benefit the general scope of oncology. Schwann cells have recently been shown to facilitate cancer progression through cytokine-mediated interaction with immune cells and other cells in the tumor microenvironment. This project will delineate the important role of the STING pathway in Schwann cells in shaping the immune landscape of tumors and may be a novel therapeutic target.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010116
Entities
People
- Jay F Pundavela
Organizations
- United States Army