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Beneficial Impact of CCL2 and CCL12 Neutralization on Experimental Malignant Pleural Effusion.doc

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Beneficial Impact of CCL2 and CCL12 Neutralization on Experimental Malignant Pleural Effusion

BeneficialImpactofCCL2andCCL12Neutralizationon ExperimentalMalignantPleuralEffusion AntoniaMarazioti1.,ChrysoulaA.Kairi2.,MagdaSpella1,AnastasiosD.Giannou1,SophiaMagkouta2, IoannaGiopanou1,VassiliosPapaleonidopoulos1,IoannisKalomenidis2,LindaA.Snyder3, DimitriosKardamakis4,GeorgiosT.Stathopoulos1,2* 1Laboratory forMolecular RespiratoryCarcinogenesis,Department ofPhysiology,Faculty ofMedicine,UniversityofPatras, Rio,Achaia, Greece, 2FirstDepartment of CriticalCare andPulmonaryMedicine,University ofAthens School ofMedicine,General HospitalEvangelismos,Athens,Attica,Greece, 3JanssenRD, LLC, Oncology Discovery Research, Spring House, Pennsylvania, United States of America, 4Department of Radiation Oncology and Stereotactic Radiotherapy, Faculty of Medicine, UniversityofPatras,Rio,Achaia,Greece Abstract Using genetic interventions, we previously determined that C-C motif chemokine ligand 2 (CCL2) promotes malignant pleuraleffusion(MPE)formationinmice.Hereweconductedpreclinicalstudiesaimedatassessingthespecifictherapeutic potentialofantibody-mediatedCCL2blockadeagainstMPE.Forthis,murineMPEsorskintumorsweregeneratedinC57BL/ 6 mice by intrapleural or subcutaneous delivery of lung (LLC) or colon (MC38) adenocarcinoma cells. Human lung adenocarcinoma cells (A549) were used to induce MPEs in severe combined immunodeficient mice. Intraperitoneal antibodiesneutralizingmouseCCL2and/orCCL12,amurineCCL2ortholog,wereadministeredat10or50mg/kgevery threedays.WefoundthathighdosesofCCL2/12neutralizingantibodytreatment(50mg/kg)wererequiredtolimitMPE formation by LLC cells. CCL2 and CCL12 blockade were equally potent inhibitors of MPE development by LLC cells. CombinedCCL2andCCL12neutralizationwasalsoeffectiveagainstMC38-inducedMPEandprolongedthesurvivalofmice in both syngeneic models. Mouse-specific CCL2-blockade limited A549-caused xenogeneic MPE, indicating that host- derived CCL2 also contributes to MPE precipitation in mice. The impact of CCL2/12 antagonism was associated