Researches On Microvesicles Generated By Micelles Lysing Tumor Cells With High Affinity For Phosphatidylserine In Immunotherapy

Tumor-derived microvesicles retain the characteristics of tumor cells,including tumor-associated antigens,adhesion molecules and nucleic acids,which can be leveraged as a universal tumor vaccine platform for cancer prevention or therapy.However,natural tumor microvesicles also carry a variety of immunosuppressive molecules,such as phosphatidylserine(PS),which block immune activation signaling.Abundant PS on the surface of tumor microvesicles induces immune tolerance,impedes immune response and promotes tumor immune escape during tumor progression,which weakens the vaccine’s therapeutic effect.In this paper,we propose a strategy of using liposomes with high affinity to PS to target and shield PS on the membrane of tumorderived microvesicles to form engineered tumor microvesicles and improve the efficacy of tumor vaccines.Through comparative study,the immune activation effect of engineered tumor microvesicles in vitro and in vivo experiments was evaluated.The specific research content is as follows:Microvesicles produced by UV-irradiated tumor cells(UV-MVs)were used as tumor vaccines for comparative study,and their surface is rich in PS.The cationic liposome FaZn containing zinc-di-(2-picolyl)amine(Zn-DPA)unit interacted with tumor cells and successfully induced tumor cells to produce engineered tumor microvesicles with partially shielded PS(FaZn-MVs).Compared with UV-MVs,FaZnMVs could more effectively promote the maturation of dendritic cells at the same dose,and reprogram the phenotype of M2 macrophages to M1 macrophages,which is beneficial to remodel the tumor microenvironment.In vivo studies showed that FaZnMVs could induce more efficient immune activity compared with UV-MVs.Combined with PD-L1 inhibitors,the synergistic effect more sufficiently promoted anti-tumor immunity and exerted the efficiency of tumor vaccine.Finally,the endogenous tumor vaccine study using FaZn in the orthotopic tumor model showed that the FaZn-MVs generated in situ could also provoke potent immune activation.This study demonstrated the potential application of the engineered tumor microvesicle vaccine platform in enhancing immunotherapy.