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 - Funding Information:
We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO for the use of the Shared Resources including Tissue Procurement Core and Small-Animal Cancer Imaging. We thank D. Schwab and S. Myles of the Department of Radiation oncology for clinical trial enrollment and patient samples. We thank B. Goetz from the Tissue Procurement Core and P. Liu from the Genome Technology Access Center. We thank K. Duncan and J. Prior for help with Bio Luminescence Imaging. We thank the Department of Radiation Oncology for shared resources and animal facilities. We thank Incyte and Calithera for providing CB1158 with a material transfer agreement between Incyte and Calithera and Washington University. Research reported in this publication was supported in part by the Washington University Radiation Oncology Departmental Seed Grant (J.H.) and another seed grant (J.H.) from the Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and the Washington University Institute of Clinical and Translational Sciences, which is, in part, supported by an NCATS Clinical and Translational Sciences Award (#UL1 TR002345). The Siteman Cancer Center is supported in part by an NCI Cancer Center Support grant no. P30 CA091842. Additional support was provided by the Barnard Cancer Institute.
Funding Information:
Acknowledgments:W ethanktheAlvinJ.SitemanCancerCenteratW ashington University SchoolofMedicineandBarnes-JewishHospitalinSt.Louis,MOfortheuseoftheShared ResourcesincludingTissueProcurementCoreandSmall-AnimalCancerImaging.W ethank D.SchwabandS.MylesoftheDepartmentofRadiationoncologyforclinicaltrialenrollment andpatientsamples.W ethankB.GoetzfromtheTissueProcurementCoreandP .Liufromthe GenomeT echnology AccessCenter.W ethankK.DuncanandJ.PriorforhelpwithBio LuminescenceImaging.W ethanktheDepartmentofRadiationOncologyforsharedresources andanimalfacilities.W ethankIncyteandCalitheraforpro viding CB1158withamaterial transferagreementbetweenIncyteandCalitheraandW ashington University.Funding: Research reported in this publication was supported in part by the W ashington University RadiationOncologyDepartmentalSeedGrant(J.H.)andanotherseedgrant(J.H.)fromtheAlvin J.SitemanCancerCenter,Barnes-JewishHospital,andtheW ashington UniversityInstituteof ClinicalandTranslationalSciences,whichis,inpart,supportedbyanNCA TS Clinicaland TranslationalSciencesA ward(#UL1TR002345).TheSitemanCancerCenterissupportedinpart byanNCICancerCenterSupportgrantno.P30CA091842.Additionalsupportwasprovidedby theBarnardCancerInstitute.Authorcontributions:S.G.plannedtheexperimentsand performedtheflowcytometricanalysisandanimalstudies.S.T .performedflowcytometric analysisandanimalstudies.E.T .analyzedscRNAdata,N.M.analyzedRNA-seqdata,andF .F .and R.A.designedtheRNA-seqstudies.X.W ., M.I.,andJ.Z.analyzedtheRNA-seqdata.D.D.andD.H. designedstudiesandanalyzeddata.D.T .andJ.H.conceptualizedanddesignedexperiments andsupervisedthestudy.TheinitialdraftwaswrittenbyS.G.,D.T ., andJ.H.,andallauthors participated in reviewand editing of the manuscript. Competing interests: The authors declarethattheyhav enocompetinginterests.Dataandmaterialsavailability:Alldata associatedwiththisstudyarepresentinthepaperortheSupplementaryMaterials.CB1158was providedunderamaterialtransferagreementbetweenW ashington UniversityandIncyteand Calithera.TheprocessedRNA-seqdataaredepositedinEuropeanNucleotideArchivewith accessionnumberERP140686.ThedatacodehasbeendepositedinZenodowiththeaccession number7368269.
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 -