M1-like Macrophage-derived Exosome Vaccine For Enhanced Cancer Immunotherapy By Mediating Tumor Microenvironment

The cancer seriously threatens human life and health for its high incidence and death rate.Tumor immunotherapy is a new treatment method after surgery,radiotherapy and chemotherapy,which brings expectation for the complete eradication of cancer.Tumor vaccine induces tumor-specific immune response through tumor antigen,which has lower toxicity and side effects than other immunotherapies.However,the immunosuppressive tumor microenvironment（TME）is one of the main factors leading to the poor effect of tumor immunotherapy,and has become a major obstacle to tumor immunotherapy.Therefore,how to change the tumor microenvironment immunosuppression is one of the key issues to improve the effect of tumor immunotherapy.Tumor-associated macrophages（TAM）ocuppy a large proportion in TME,According to the different functions,TAM is divided into M1 type and M2 type,and the main TAM is M2macrophages.M2 macrophages play an important role in the growth,invasion and metastasis of tumor,which are characterized by promoting tumor development and suppressing immunity.However,M1 macrophages have the opposite function to M2 macrophages,which inhibit the growth,invasion and metastasis of tumors.Therefore,the polarization of M2 to M1 can restore the antitumor effect of macrophages,and alleviate the immunosuppression of TME and enhance the effect of immunotherapy.Exosomes are extracellular vesicles produced during the normal life activities of cells,which carry the complex RNA and protein of the parent cell,and have some physiological characteristics of the parent cell.For example,exosomes derived from M1 macrophages have the physiological functions of M1 macrophages,and can exhibit the ability to polarize macrophages to the M1 phenotype.Based on this,we designed an exosome vaccines from M1 macrophage(M1_OVA-Exos).First,the mouse primary macrophages（M0）were obtained by peritoneal lavage,and then they were polarized into M1 type macrophages by lipopolysaccharide（LPS）.Then the ovalbumin（OVA）was taken up by M1 macrophages.Finally,the exosomal vaccine M1_OVA-Exos was obtained by ultrafiltration.The experimental results showed that the M1_OVA-Exos reached the tumor site.On the one hand,M2 macrophages can be polarized into M1 macrophages,play the role of killing tumor cells,improve the immunosuppressive TME,increase the infiltration of T cells into tumor tissue.Moreover,as a tumor vaccine,M1_OVA-Exos activates immune response,realizes cellular immunity and humoral immunity,effectively inhibits tumor growth and metastasis.