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bioRxiv · 10.1101/2022.11.14.516419

Inducible co-stimulatory molecule (ICOS) alleviates Paclitaxel induced peripheral neuropathy via an IL-10-mediated mechanism in female mice

Sankaranarayanan, I.·Tavares-Ferreira, D.·Mwrigi, J. M.·Mejia, G. L.·Burton, M. D.·Price, T. J.
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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a primary dose-limiting side effect caused by antineoplastic agents, such as paclitaxel. This causes damage to peripheral nerves and the dorsal root ganglia (DRG). Currently, there are no effective treatments for CIPN, which can lead to long-term morbidity in cancer patients and survivors. Neuro-immune interactions occur in CIPN and have been implicated both in the development and progression of the disease and disease resolution. We investigated the potential role of Inducible co-stimulatory molecule (ICOS) in the resolution of CIPN pain-like behaviors in mice. ICOS is an immune checkpoint molecule that is expressed on the surface of activated T cells and promotes proliferation and differentiation of T cells. We found that intrathecal administration of ICOS agonist antibody (ICOSaa) alleviates mechanical hypersensitivity caused by paclitaxel and facilitates the resolution of mechanical sensitivity in female mice. Administration of ICOSaa reduced astrocyte-gliosis in the spinal cord and satellite cell gliosis in the DRG of mice previously treated with paclitaxel. Mechanistically, ICOSaa intrathecal treatment promoted pain resolution by increasing interleukin 10 (IL-10) expression in the dorsal root ganglion. In line with these observations, blocking IL-10 receptor (IL-10R) activity occluded the effects of ICOSaa treatment on CIPN behavior in female mice. Suggesting a broader activity in neuropathic pain, ICOSaa also partially resolved mechanical hypersensitivity in the spared nerve injury (SNI) model. Our findings support a model wherein ICOSaa administration induces IL-10 expression to facilitate neuropathic pain relief in female mice. ICOSaa treatment is in clinical development for solid tumors and given our observation of T cells in the human DRG, ICOSaa therapy could be developed for combination chemotherapy - CIPN clinical trials. HighlightsO_LIICOS agonist antibody (ICOSaa) promotes pain resolution in female mice C_LIO_LIDRG T cells appear to enter an anti-inflammatory phenotype by ICOSaa treatment C_LIO_LIICOSaa treatment increases DRG levels of IL-10 cytokine C_LIO_LIICOSaa effects in female mice are blocked by IL-10 sequestering treatment C_LI

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Sankaranarayanan, I., Tavares-Ferreira, D., Mwrigi, J. M., Mejia, G. L., Burton, M. D., Price, T. J.. 2022-11-14. Inducible co-stimulatory molecule (ICOS) alleviates Paclitaxel induced peripheral neuropathy via an IL-10-mediated mechanism in female mice. https://doi.org/10.1101/2022.11.14.516419

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