| Background:Oxaliplatin-containing chemotherapy regimens are recommended as first-line treatment by National Comprehensive Cancer Network.Unfortunately,intrinsic or acquired resistance to oxaliplatin-based combinations still is the major cause of treatment failure.For this reason,it is paramount importance to elucidate underlying mechanism of this phenomenon and uncover better ways to fight cancer.Increasing evidences have proved that both tumor immune microenvironment and myeloid-derived suppressor cells(MDSCs)play important role in chemosensitivity.The frequency and differentiation of MDSCs in chemotherapy-resistant have been concerned.The differentiation of MDSCs into M1/M2-like macrophages would further take a positive or negative effect on antitumor activity.Immune agents,including Toll-like receptors(TLRs)agonists attain widespread attention due to their unique advantage in activition of adaptive immunity and innate immunity.Recently,several studies suggested that resiquimod(R848)could modify the frequency and differentiation of MDSCs.Therefore,our study discovered the immunological mechanism of oxaliplatin-resistance and demonstrated the undering immunologic adjuvant of TLR7/8 agonist in chemotherapy for colorectal cancer.Methods:1.Oxaliplatin administration inhibited MDSCs differentiation into Ml-like macrophages:We evaluate the effectiveness of oxaliplatin on tumor and MDSCs through flow cytometry,qPCR,cytotoxicity and apoptosis assay.2.R848 reverses mis-regulatory differentiated effect of oxaliplatin on MDSCs by elevating Ml-like macrophages:We evaluate the effectiveness and modulatory function of R848+oxaliplatin on tumor and MDSCs through H&E,immunohistochemical staining,flow cytometry,qPCR,cytotoxicity and apoptosis assay.3.The physichemical properties and characterization of PsePt and PsePt@R848.The average diameter,polymer dispersity indexs and zeta potentials of PsePt and PsePt@R848 were assessed by nanoparticle size analyzer.The drug loading rate and drug release rate were determined by ICP-MS and high performance liquid chromatography.Results:1.Oxaliplatin remarkably retarded tumor progression,reduced MDSCs infiltration and M1-like macrophages differentiated from MDSCs in tumor site.In vitro,oxaliplatin inhibited the MDSCs polarizated into M1 phenotype macrophages and secreted pro-inflammatory cytokines TNF-α.2.R848 reverses oxaliplatin resistance by polarizing MDSCs into M1-like macrophages and elevating pro-inflammatory cytokines including TNF-α and IL-1β.3.The combination of oxaliplatin and R848 displayed stronger tumor growth inhibitory effect and reversed oxaliplatin-related immunosuppression.4.The average diameters of PsePt and PsePt@R848 were 183.8±2.5 nm and 225.9±17.4 nm,the polymer dispersity indexs and zeta potentials were 0.25±0.03,-25.1±2.2 mV and 0.33±0.14 and-20.7±0.9 mV,respectively.Drug release experiments showed that PsePt and PsePt@R848 were reduction sensitive.Conclusion:1.Oxaliplatin inhibited MDSCs differentiated into M1-like macrophages2.Resiquimod reversed oxaliplatin-resistance by polarizing MDSCs into M1-phenotype3.PsePt and PsePt@R848 display excellent nano-propertites. |
