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bioRxiv · 10.1101/2024.06.20.599939

Targeting MDSC-HTR2B to Improve Immune Checkpoint Inhibitors in Breast to Brain Metastasis

Iyer, M.·Das, D.·Baugh, A.·Shah, P.·Nakamura, B.·Sedighi, S.·Reed, M.·Jang, J.·Chow, F.·Torres, E. R.·Neman, J.
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Abstract

Myeloid Derived Suppressor Cells (MDSCs) support breast cancer growth via immune suppression and non-immunological mechanisms. Although 15% of patients with breast cancer will develop brain metastasis, there is scant understanding of MDSCs contribution within the breast-to-brain metastatic microenvironment. Utilizing co-culture models mimicking a tumor-neuron-immune microenvironment and patient tissue arrays, we identified serotonergic receptor, HTR2B, on MDSCs to upregulate pNF-{kappa}B and suppress T cell proliferation, resulting in enhanced tumor growth. In vivo murine models of metastatic and intracranial breast tumors treated with FDA-approved, anti-psychotic HTR2B antagonist, clozapine, combined with immunotherapy anti-PD-1 demonstrated a significant increase in survival and increased T cell infiltration. Collectively, these findings reveal a previously unknown role of MDSC-HTR2B in breast-to-brain metastasis, suggesting a novel and immediate therapeutic approach using neurological drugs to treat patients with metastatic breast cancer.

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Iyer, M., Das, D., Baugh, A., Shah, P., Nakamura, B., Sedighi, S., Reed, M., Jang, J., Chow, F., Torres, E. R., Neman, J.. 2024-06-25. Targeting MDSC-HTR2B to Improve Immune Checkpoint Inhibitors in Breast to Brain Metastasis. https://doi.org/10.1101/2024.06.20.599939

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