Research On Self-assembled Epitope Vaccine For Tumor Immunotherapy

In the past decades,with the development of various immune checkpoint inhibitors and chimeric antigen receptor T cell therapies,immunotherapy has revolutionized the treatment of many cancers.Among them,antigen peptide vaccine has been identified as a promising strategy in cancer immunotherapy.However,the therapeutic effect is greatly reduced by low antigen immunogenicity.Besides,the physical and chemical properties of peptides and the variability,flexibility and feasibility of vaccine formulations are also a major challenge for the current vaccine design.Therefore,improving the immunogenicity of antigen polypeptides,improving the immunosuppressive microenvironment,and simplifying vaccine formulations are problems that need to be solved urgently in the preparation of polypeptide vaccines.Based on these,this article takes the self-assembled epitope vaccine as the main line and aims to enhance its anti-tumor effect.The following work has been carried out:In order to improve the immunogenicity of the antigen,the Toll-like receptor 9agonist(TLR9)CpG was thought of adding to the self-assembled vaccine,and reversed immunosuppression by combining immune checkpoint inhibitor1-methyltryptophan(1-MT).Indoleamine 2,3-dioxygenase(IDO)is a key metabolic enzyme that can significantly inhibit effector T cell responses,while 1-MT acts as IDO inhibitor.In this work,cationic polymer-lipid hybrid nanovesicle(P/LNV)-based liposomes are designed to simultaneously deliver tumor vaccine composed of anionic antigen epitope/CpG(AE/CpG)and 1-MT.On the one hand,it increases the immunogenicity of polypeptide antigens and blocks immune checkpoints.On the other hand,the P/LNV liposomes effectively enhanced the uptake of vaccines by dendritic cells(DCs),promoted the maturation of DCs,and mediated antigen-specific cytotoxic T lymphocytes(CTL)reactions against B16-OVA tumors.More importantly,compared with the untreatment or an individual therapy modality,the combination immunotherapy showed significantly higher therapeutic efficiency towards melanoma in vivo.Mechanistically,the co-delivery system can cause a strong tumor-specific T cell response and increase the infiltration of CD8~+T cells in the tumor and draining lymph nodes.Altogether,the cationic liposome can stimulate anti-tumor T cell immunity while reversing the tumor immunosuppressive microenvironment,providing a promising delivery platform for cancer immunotherapy.In the design of tumor vaccines,immune adjuvant is usually selected to improve immunogenicity.In order to simplify the vaccine design,epitope vaccines that does not require immune adjuvants and delivery systems are designd.Specifically,the supramolecular co-assembly of epitope-conjugated peptides(ECPs)targeting CD8 or CD4 T cell receptors was successfully prepared the nanofiber hydrogel vaccine.This approach provided precise and tunable loading of peptide antigens in nanofibers,which notably increased the antigen uptake,cross-presentation,and activation of DCs.Immunization in mice indicated that the co-assembled peptide hydrogel did not induce local inflammation responses and elicited significantly promoted T-cell immunity by activating the My D88-dependent NF-κB signaling pathway in DCs.Vaccination of mice using co-assembled peptide vaccine stimulated both enhanced CD8 and CD4 T cells against EG.7-OVA tumors without additional immunoadjuvants or delivery systems,and resulted in a more remarkable cancer immunotherapy efficacy,compared with free peptide vaccine or aluminum-adjuvanted peptide formulation.Altogether,peptide co-assembly demonstrated by three independent pairs of ECPs is a facile,customizable,and chemically defined approach for co-delivering peptide antigens in self-adjuvanting hydrogel vaccines that could induce stronger anticancer T-cell responses.