Lipid-peptide Nanovaccine/nanodrug Targeting Antigen Presenting Cells For Cancer Immunotherapy

As one of the most incurable disease,cancer has been a huge threat to human health.At present,the study of cancer therapy is one of the most influential,most challenging and most economically valuable ones in the field of life sciences.In addition to surgery,chemotherapy and radiotherapy,cancer immunotherapy has drawn more and more attention,and is considered promising to completely cure cancerRecent studies have found that the immunoediting effect of tumors inhibite the activation of the adaptive immune response through leading the dysfunction of APCs.Therefore,restoring the normal function of APCs for the activation of antigen-specific immune response against tumor cells is a major focus of cancer immunotherapy.However,due to the lack of efficient targeting strategy,the drugs are often not adequately ingested by target APCs or captured by functional APCs instead,leading to difficulty in achieving the desired therapeutic effect and even autoimmune diseases.Therefore,developing high efficient APC targeting technology is of great value for the optimization of the APC-based cancer immunotherapy.Due to the tissue distribution and differentiation character of APCs such as dendritic cells(DCs)and tumor-associated macrophages(TAMs),the APC-targeted drug delivery is also a challenging task.In this study,in which DCs and TAMs are main research object,we developed a nanoparticle(NP)that targeted to DCs in lymph node in vivo and effectively delivered antigen peptide to the DCs,and obtained great anti-tumor effec.In addition,an M2 polarized TAM(M2-like TAM)targeting NP was developed and the NP-based molecular-targeted cancer immunotherApeutic strategy was established.The detailed results are as followed:1)The experimental results show that a-Ap-FNP can targeted deliver antigen peptide to bone marrow DCs(BMDCs)in vitro and deliver antigen peptide directly to SR-B1 highly expressing mDCs with poor phagocytosis ability through SR-B1 and the efficiency is at least 20 folds higher than that of free antigen peptide.2)The ex vivo DC-based vaccine was optimized using a-Ap-FNP.Through mDC-targeted antigen delivery character of a-Ap-FNP,we improved the incubation schedule by using a-Ap-FNP to directly incubate with mDC instead of imDC,our optimization eliminates the need to stimulate imDC maturation and achieve better efficacy.3)When the CpG-ODN was loaded,a-Ap-FNP-CpG blocked the E.G7-OVA tumor growth and decreased the average tumor size of melanoma by 65%.4)M2NPs high efficiently delivered siCD115(siRN A)to the cytoplasm of M2-like TAMs.M2NP-siCD115 specifically depleted 44%of M2-like TAMs in melanoma tumor,decreased 84%of the expression of immunosuppressive cytokine IL-10,increased the CD8+ T cell infiltration by 3.5 folds and eventually decreased the average tumor size by 82%.In summary,in this study we developed targeted NPs for the two key APCs(DCs and TAMs),respectively,and both showed excellent targeting effects.a-Ap-FNP,by virtue of its particle size and targeting properties,delivers antigen peptides and immune adjuvants to DCs in the lymph nodes to inhibit tumor growth.M2NP as a M2-like TAMs targeting delivery platform,the use of its dual-targeting unit to carry siRNAto M2-like TAMs,which specifically eliminated the M2-like TAM and activated anti-tumor immune response,inhibited Tumor growth.Therefore,this study provides a new targeting and treatment strategies for APC-based tumor immunotherapy.