Research Of Advanced Cancer Immunotherapy Strategies And Explorations Of Cancer Therapeutic New Targets

Malignancy tumors are a kind of cambium which mutate from normal cells and are able to proliferate and expand continuously.Due to their high morbidity and lethality,malignancy tumors are greatly threatening human beings' lives nowadays.In order to cure tumors,researchers and doctors have tried to develop many kinds of strategies,including surgery,chemotherapy,radiotherapy,and immunotherapy.However,lack of deep understanding of the whole details during tumor treatment and streatgies to prevent tumor drug resistance and recurrence,not all patients can benefit from these traditional therapies.On account of this,we first propose to utilize high efficiency delivery capbility and specific optical property of advanced nano-materials for dendritic cell-based immunotherapy,to realize in vivo tracking of dendritic cells with highly sensitivity and stimulating antigen-specific immune responses at the same time.The application of nanotechnology will bring new detailed information during immunotherapy.Besides,we focus on the one of the key points of drug resistance and recurrence,tumor stem cells.Excitedly,by analyzing the mice tumor chip assay and clinical database,we find a potential new therapeutic target for glioma target therapy,Engrailed gene,and then do the proof tests.This finding will give a new direction in tumor target therapy.The major contents and conclusions are shown as follows.Chapter 1: We firstly conduct a systematic introduction of the tumorigenesis and progression of malignancy tumors and various modern cancer therapies,including surgery,chemotherapy,radiotherapy,and advanced immunotherapy and target therapy,as well as their advantages and disadvantages.Then we give an overview of new nanotechnology methods and their advantages in cancer therapy.Finally,we focus on the lastest developments of tumor treatment with cancer stem cells and their hints in finding therapeutic targets.Chapter 2: Cancer immotherapy,especially tumor vaccines,has been well developed these years because of its specificity and low-toxicity.As an important part of immunotherapy,dendritic cell(DC)vaccines have shown therapeutic effect in clinical cases.Therefore we have tried to design a nanocarrier-antigen complex for tracking the happening of immune reaction progress and enhancing immune responses and discuss its applications in DC-based immunotherapy.It is discovered firstly that ovalbumin can be adsorbed on the surface of dual-polymer-coated UCNPs via electrostatic interaction,forming nanoparticle-antigen complexes,which are efficiently engulfed by DCs and induce DC maturation and cytokines release.Highly sensitive in vivo upconversion luminescence(UCL)imaging of nanoparticle-labeled DCs has been successfully carried out then,observing the homing of DCs during the immune response after injection.In addition,strong antigen-specific immune responses including enhanced T cell proliferation,interferon gamma production and cytotoxic T lymphocyte(CTL)-mediated responses have been proved to be induced by this nanoparticle-pulsed DC vaccine.Chapter 3: Gliomablastoma,one of the most malignancy tumors that human beings suffer from,is not sensitive to chemo-and radio-therapy,and easily relapses after traditional treatment.It is widely accepted that the existence of glioma stem cells(GSCs)is one of the main reasons for this phenomenon.So investigating specific therapeutic targets of glioma stem cells is the key pathway and core research project for glioma treatment.By comparing high-throughput sequencing data of relevant glioma and GSC samples,we find out that Engrailed gene family is one of the top high expression genes when compared to control samples.Also,there is a significant positive correlation between tumor grade and the expression level of Engrailed genes in patient database and a negative correlation between the patient survival and Engrailed genes expression level.In proof test,on the one hand,Engrailed gene knocking down slows down the growth of glioma cell lines as well as cell growth and self-renewal ability of GSCs.On the other hand,overexpression of EN1 in U251 cells promotes cell migration and chemo-drug resistance,while overexpression of En1 in GSCs promotes self-renewal ability and kills tumor bearing mice rapidly.Meanwhile,GSCs show lower differentiated state in transplantation samples.All these data indicate that Engrailed gene could be an oncogene in glioma and become a potential therapeutic target in glioma treatment.To summarize,in this article,we firstly mainly discuss and develop an advanced immunotherapy strategy based on nanomaterials which can realize tracking the progress of immune responses with highly sensitivity and enhancing antigen-specific immune responses at the same time within dendritic cell tumor vaccines,and this strategy gives new ideas about how to combine nanotechnology and cancer therapy.Besides,we discover a new potential therapeutic target,Engrailed gene,by analyzing mice glioma stem cell sequencing results and clinical database,and proved the important function of this gene in glioma,which explores a new direction for glioma target therapy.