TY - JOUR
T1 - Radiation-induced circulating myeloid-derived suppressor cells induce systemic lymphopenia after chemoradiotherapy in patients with glioblastoma
AU - Ghosh, Subhajit
AU - Huang, Jiayi
AU - Inkman, Matthew
AU - Zhang, Jin
AU - Thotala, Sukrutha
AU - Tikhonova, Ekaterina
AU - Miheecheva, Natalia
AU - Frenkel, Felix
AU - Ataullakhanov, Ravshan
AU - Wang, Xiaowei
AU - DeNardo, David
AU - Hallahan, Dennis
AU - Thotala, Dinesh
N1 - Publisher Copyright:
Copyright © 2023 The Authors.
PY - 2023/1/25
Y1 - 2023/1/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85146864622&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abn6758
DO - 10.1126/scitranslmed.abn6758
M3 - Article
C2 - 36696484
AN - SCOPUS:85146864622
SN - 1946-6234
VL - 15
JO - Science translational medicine
JF - Science translational medicine
IS - 680
M1 - eabn6758
ER -