The Design Of Nanocarriers For Potentiating The Efficacy Of Dendritic Cells And Immunotherapey

Tumor immunotherapy is a new type of clinical treatments for cancer and has been widely concerned by researchers in recent years.Among them,dendritic cell(DC)is the most powerful antigen presenting cell,which acts as the “sentinel” of antigen recognition in vivo and the key factor to start the normal tumor-immune cycle.Therefore,DC cell is an important target of tumor immunotherapy.To further improve the antitumor efficiency of immunotherapy,activating DC cells and enhancing the antigen presentation function by nanotechnology are the focus of current research.In this paper,two nano systems were designed to generate and targeted-delivery of antigens by external stimulus(near infrared light and alternating magnetic field)for the maturation of DC cells and improve the efficiency of immunotherapy.The main contents of this dissertation are described in two parts as below:1.Immune checkpoint blocking antibodies have shown great success in the clinic,but their low response rate in patients remains a huge challenge.Inspired by the capability of immunogenic cell death to activate DC cells,we developed a corn-like Au/Ag nanorod(Au/Ag NRs),which showed remarkable photothermal/photodynamic effect under 1064 nm light irradiation and induced the ICD of tumor cells.During the process of ICD,the release of damage associated molecular patterns stimulated DC cells to be mature as well as handle and presented the antigens to T cells for the following anti-tumor immune response.Furthermore,Au/Ag NRs synergized with ICB antibodies can efficiently inhibit distant tumor growth and lung metastases.Besides,the combination of a CTLA-4 and Au/Ag NRs elicited a strong immunological memory effect that protected against tumor recurrence.This Au/Ag NRs nano system provides new avenues to improve the efficacy of immunotherapy by activate the immune response of DC cells.2.Tumor vaccines consisting of tumor antigens and immune adjuvants are a promising cancer treatment modality.Especially,the one which can generate tumor antigens in situ and then delivery the antigens as well as immune adjuvants to lymph nodes is a more simple and effective strategy.However,how to realize the idea remans to a huge challenge.On the basis of the study about in situ antigen releases by photothermal/photodynamic effect,we constructed an in situ programmable vaccine consisting of two nanodrugs,Tu-NP and Ln-NP.Tu-NP(～100nm)generated a large number of antigens under alternating magnetic field,and Ln-NP(～30 nm)encapsulating adjuvant R848 captured the partial generated antigens.Meanwhile,the the small scale of Ln-NP improved the enrichment in lymph nodes,thus promoting the antigen presentation of DC cells to initiate potent anti-tumor immune response.Notably,combined with an a CTLA-4,this nano system completely eradicated distant tumors in some mice,exerted a long-term immune memory effect and inhibited tumor metastasis.In this study,two nano systems of different scales were designed to effectively combine the processes of generating tumor antigens in situ,capturing antigens,and co-delivering to lymph node with immune adjuvants,which provides a new strategy for the construction of in situ tumor vaccines.