Deciphering and Targeting the Schwannoma‐Neuron‐Macrophage Crosstalk for the Treatment of Schwannomatosis and Associated Pain

ABSTRACT Non‐NF2 Schwannomatosis (SWN) is a genetic disorder characterized by multiple non‐malignant schwannomas growing on the spine and peripheral nerves. Patients with SWN overwhelmingly present with intractable chronic pain. There are no FDA‐approved drugs to halt tumor growth or alleviate pain. Research on SWN is hindered by the lack of clinically relevant models. We established patient‐derived SWN cell lines from patients with varying pain levels and developed orthotopic patient‐derived xenograft models that reproduce patients’ pain responses. We further developed a novel dorsal root ganglia (DRG) imaging model for longitudinal intravital imaging of macrophage infiltration into the DRG and sensory neuron pain response. Leveraging these novel models, we found that Schwannomas grown distantly in the peripheral nerve caused an influx of macrophages into the DRG. These macrophages in the DRG caused pain via overproducing IL‐6. Treatment with anti‐IL‐6 antibody reduced pain but had modest efficacy in tumor control. We identified epidermal growth factor receptor (EGFR) signaling as a key driver of schwannoma growth and an escape mechanism from anti‐IL6 treatment. Finally, we found that combining IL‐6 and EGFR blockade effectively controlled pain and tumor growth simultaneously in SWN models. In summary, we elucidated the cellular and molecular crosstalk between schwannoma (HMGB1), neuron (CCL2), and macrophage (IL‐6) in driving pain, and identified the EGF signaling pathway as a driver of SWN tumor progression, thereby uncovering novel therapeutic targets that may improve clinical management of SWN.