Radiation-induced circulating myeloid-derived suppressor cells induce systemic lymphopenia after chemoradiotherapy in patients with glioblastoma

Severe and prolonged lymphopenia frequently occurs in patients with glioblastoma after standard chemoradiotherapy and has been associated with worse survival, but its underlying biological mechanism is not well understood. To address this, we performed a correlative study in which we collected and analyzed peripheral blood of patients with glioblastoma (n = 20) receiving chemoradiotherapy using genomic and immune monitoring technologies. RNA sequencing analysis of the peripheral blood mononuclear cells (PBMC) showed an elevated concentration of myeloid-derived suppressor cell (MDSC) regulatory genes in patients with lymphopenia when compared with patients without lymphopenia after chemoradiotherapy. Additional analysis including flow cytometry and single-cell RNA sequencing further confirmed increased numbers of circulating MDSC in patients with lymphopenia when compared with patients without lymphopenia after chemoradiotherapy. Preclinical murine models were also established and demonstrated a causal relationship between radiation-induced MDSC and systemic lymphopenia using transfusion and depletion experiments. Pharmacological inhibition of MDSC using an arginase-1 inhibitor (CB1158) or phosphodiesterase-5 inhibitor (tadalafil) during radiation therapy (RT) successfully abrogated radiation-induced lymphopenia and improved survival in the preclinical models. CB1158 and tadalafil are promising drugs in reducing radiation-induced lymphopenia in patients with glioblastoma. These results demonstrate the promise of using these classes of drugs to reduce treatment-related lymphopenia and immunosuppression. Description Irradiation of glioblastoma induces aberrant myelopoiesis generating the release of MDSC from bone marrow causing systemic lymphopenia. Limiting lymphopenia in GBM Lymphopenia, a lack of white blood cells, frequently occurs in patients with glioblastoma (GBM) after chemoradiation therapy, and its association with worse survival is not well understood. To investigate this, Ghosh et al. performed analyses on peripheral blood from 20 patients treated for GBM. They identified an elevated concentration of myeloid-derived suppressor cells (MDSC) in patients with lymphopenia after treatment. They developed murine models to demonstrate a causal relationship between radiation-induced MDSC and lymphopenia. Last, they showed that pharmacologic inhibition of MDSC abrogated lymphopenia and improved survival in mice, suggesting these classes of drugs as a potential treatment to reduce lymphopenia in patients with GBM.—DH

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