The Study On Mechanism Of MDSCs-mediated Tumor Recurrence After Ablation And Strategy That Nanodrugs Enhanced Anti-tumor Recurrence After Ablation

With the progression of population aging and the changes of human-living environment,the incidence and mortality of cancer are increasing year by year,and it has become the main cause of death for Chinese people,which seriously affects the health and life quality of the people.At present,there are some traditional treatment modes for curing tumor,including surgical resection,radiotherapy,chemotherapy and so on.In theory,surgical resection is the first choice for the eradication of tumor.However,during the clinical practice,because of the poor tolerance,age,special location of tumor and other chronic diseases in tumor patients,they have lost the chance of surgical resection.In recent years,with the development of local minimally invasive therapy,thermal ablation,as a kind of minimally invasive therapy which can inactivate tumor in situ,have been paid more and more attention.Radiofrequency ablation(RFA),as a new technique of minimally invasive therapy,has been widely used in many solid tumors.The new treatment choices are provided for some cancer patients who have lost the chance of resection,especially heptacellular carcinoma(HCC)and hepatic metastasis.Although radiofrequency ablation is effective,the tumor recurrence after ablation is still a great challenge in clinical practice.At present,the mechanism of tumor recurrence after ablation was not completely known.However,according to previous studies,the tumor recurrence after ablation tumor may be mainly related to the alteration of the immune microenvironment and the residual after ablation.Previous study shows that the myeloid-derived suppressor cells(MDSCs),as an immature heterogeneous myeloid-derived cells,have the great capability to inhibit the immune response,which plays an important role in the immune tolerance of tumor and has a significant correlation with the prognosis of the tumor.The effects of MDSCs on the changes of tumor immune microenvironment and tumor recurrence after RFA was unknown.Therefore,the first part in this study will mainly discuss the effects of MDSCs on the changes of tumor immune microenvironment and the role of tumor recurrence after RFA,In this part,the results found that incomplete RFA treatment induced MDSCs infiltration and enhanced immune suppression,and tumor progression was associated with increased tumor-infiltrating MDSCs in CT26 colon tumor models.The depletion of MDSCs by GR-1 Abs exerts therapeutic effects on tumor regression by regulating the shift from Th2 to Thl.At the same time,in order to overcome the residual after RFA,recent pre-clinical studies showed that the combination of RPA with nanoparticles intravenously injected(IV)can further enlarge the zones of coagulation necrosis.However,the therapeutic efficacy of combination therapy was not ideal in clinical trails.For example,an intermational multicenter clinical trial showed RFA combined IV thermosensitive liposomal doxorubicin did not increase the progression-free survival(PFS)and overall survival(OS)in the overall study population of hepatocellular carcinoma(HCC).And,26%of HCC patients in this clinical trial suffered many side effects.In order to further analyze its causes and achieve better therapeutic efficacy,the second part in this study will mainly focus on discuss the strategy that nano-drugs enhanced anti-tumor recurrence after ablation.In this part,the results found that the combination of RFA with nano-drugs intratumorally injected(IT)led to much deeper and greater intratumoural drug penetration and accumulation,resulting in better therapeutic efficacy.Compared to IV or IT chemotherapy alone,the combination of RFA decreased toxicity,especially in the IT+RFA group.At the same time,in order to accurately position tumor margin so as to reduce the residual caused by microvascular invasion,in the third section of this part,the preliminary exploration for accurate localization of tumor margin was performed by molecular imaging based on targeted probes construted,and the favorable results have been obtained.In conclusion,based on the residual tumor recurrence after RFA,this study discussed the role and influence of MDSCs in residual tumor recurrence after RPA.and further interpreted the mechanism of residual tumor recurrence after RFA.And,in order to reduce residual tumor recurrence,the second part in this study will mainly focus on discuss the strategy that nano-drugs enhanced anti-tumor recurrence after ablation.This study will provide theoretical basis and method guidance for the further implementation of combined therapy,and provide a new strategy for the comprehensive treatment of tumor.