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1040-E Deciphering and targeting the schwannoma-neuron-macrophage crosstalk for the treatment of schwannomatosis and associated pain
  1. Zhenzhen Yin1,
  2. Limeng Wu1,
  3. Yanling Zhang1,
  4. Yao Sun1,
  5. John W Chen1,
  6. Sonu Subudhi1,
  7. Grace Lee1,
  8. Athena Wang1,
  9. Xing Gao1,
  10. Jun Ren2,
  11. Alona Muzikansky1,
  12. Anat Stemmer-Rachamimov1,
  13. Jianren Mao1,
  14. Scott R Plotkin1 and
  15. Lei Xu1
  1. 1Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
  2. 2Massachusetts General Hospital, Boston, MA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background 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, debilitating chronic pain, severe enough to cause permanent disability. The etiology of pain in SWN is not clear, and the development of novel treatments for SWN and related pain has been extremely slow and inefficient. Treatment for SWN is limited to invasive surgery, which carries significant risks of further nerve damage. No drug is currently FDA-approved to halt SWN tumor growth or ameliorate SWN-associated pain. The drivers of pain response and tumor progression in SWN are not clear - the pain is not proportionally linked to tumor size and is not always relieved by tumor resection, suggesting that mechanisms other than mechanical nerve compression exist to cause pain. SWN research is limited by the lack of clinically-relevant models.

Methods We established novel patient-derived xenograft (PDX) models and dorsal root ganglia (DRG) imaging models. Combined with single-cell resolution intravital imaging and RNASeq to study the mechanisms cause pain.

Results We discovered: i) schwannomas on the peripheral nerve cause macrophage influx into the DRG, via secreting HMGB1 to directly stimulate DRG neurons to express CCL2, the key macrophage chemokine, ii) once recruited to the DRG, macrophages cause pain response via overproduction of IL-6, iii) IL-6 blockade in a therapeutic setting significantly reduces pain but has modest efficacy on tumor growth, iv) EGF signaling is a potential driver of schwannoma growth and escape mechanism from anti-IL6 treatment, and v) combined IL-6 and EGFR blockade simultaneously controlled pain and tumor growth in SWN models.

Conclusions In summary, we deciphered the cellular and molecular crosstalk between schwannoma (HMGB1)-neuron (CCL2)-macrophage (IL-6) in driving pain response, and identified EGF pathway as driver of SWN tumor progression. Our findings prompted the initiation of phase II clinical trial (NCT05684692) for pain relief in patients with SWN.

Ethics Approval This study was approved by Massachusetts General Hospital’s Ethics Board; approval number is A3596-0.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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