LAUSR

Introduction: Neurofibromatosis Type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-Activating Protein. Inactivating NF1 mutations result in hyperactivation of RAS-mediated signaling. NF1 patients develop benign tumors on the skin and along nerves in the spinal cord and brain, and ~10% of these progress to Malignant Peripheral Nerve Sheath Tumors (MPNST). Attempts to inhibit RAS-signaling to treat MPNST have not worked in clinical trials. Surgical removal is the only cure for MPNST, which is challenging due to large tumor size and/or proximity to nerves. MPNSTs often recur, metastasize, and respond poorly to chemo- and radiotherapy. As a result, MPNSTs are the leading cause of death in NF1 patients. Immune Checkpoint Blockade (ICB) is an approach to treat inoperable, undruggable cancers. Immune checkpoint proteins (ICPs) terminate normal immune responses to prevent collateral tissue damage. Cancer cells hijack this mechanism and express ICPs to avoid immune detection. ICB disrupts this process, enhancing antitumor immunity. Monoclonal antibodies (mABs) that disrupt the interaction between Programmed Cell Death Receptor 1 (PD-1) and its ligand Programmed Cell Death Ligand 1 (PD-L1) are a widely used ICB therapy. Having a T cell-enriched hot tumor microenvironment (TME) is required for successful ICB. However, MPNSTs lack a T cell-inflamed TME and respond poorly to ICB therapy. Activation of the protein “stimulator of interferon genes” (STING) enhances anti-tumor immunity via induction of pro-inflammatory cytokines, thus increasing T cell infiltration into the TME. We hypothesized that reprogramming the MPNST TME by STING pathway activation would turn cold MPNSTs into hot tumors amenable to ICB. Methods: We treated mouse MPNSTs with STING agonist or STING agonist + anti-PD-1/anti-PD-L1 mAb. Tumor size was measured throughout treatment. The mice were sacrificed and tumor tissue was analyzed for STING pathway activation, T cell infiltration, cell proliferation, and apoptosis. MPNST allograft tumors in athymic mice were controls. Results: STING pathway activation and increased T cell presence was observed in STING agonist-treated MPNSTs compared to vehicle-treated. MPNSTs treated with STING agonist alone or STING agonist + PD-1/PD-L1 mAbs showed less tumor growth relative to vehicle. Importantly, STING agonist + PD-1/PD-L1 mAb-treated tumors showed significant cell death increase while cell proliferation remained unchanged. Interestingly, tumors in athymic mice continued to grow despite treatment suggesting the antitumor effects seen in immunocompetent mice were mediated by T cells. Conclusions: Our data show that MPNSTs can become T cell-rich tumors by activating STING signaling. Reprogramming the TME made MPNSTs susceptible to immune destruction by ICB therapy. Our studies support this novel treatment strategy for MPNST, an aggressive, deadly tumor for which no molecular therapy currently exists. Citation Format: Nipunika Somatilaka, Laasya Madana, Ali Sadek, Renee M. McKay, Lu Q. Le. STING inflames NF1 malignancies for immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5170.