Combination Of Dendritic Cell Exosomes Based Vaccine With Immune Checkpoint Blockers For Enhanced Cancer Immunotherapy

Cancer is a global public health problem and has become one of the most common and frequently-occurring diseases with the highest mortality rate in the world.Compared with traditional cancer treatment methods,tumor immunotherapy has the advantages of strong specificity,immune memory,and killing effect on primary tumors and metastatic tumors.It is a new treatment method that is expected to completely eradicate cancer.In particular,the emergence of Immune Checkpoint Blockade(ICB)therapy has equipped tumor treatment with novel and powerful "weapons",which has become the main research direction of tumor immunotherapy in the world.ICB therapy is a treatment method that blocks the immunosuppressive pathway activated by cancer cells through antibodies,but the off-target effect and low plasma half-life lead to the low efficiency ofsingle-agent treatment of cancer is only about 20%.In addition,immune-related toxic effects caused by immune checkpoint blocking drugs while reactivating the immune system is also a problem that cannot be ignored.Moreover,due to the multiple immunosuppression mechanisms and the tumor microenvironment,tumor cells are freed from the surveillance and immune killing effects of the immune system under various immune escape pathways.In summary,it is difficult to achieve effective treatment of tumors simply by removing one of the tumor's immunosuppressive pathways.How to develop a new immunotherapy system to overcome the shortcomings of single blockers such as low treatment efficiency and large toxic effects is of great research significance for the radical treatment of tumors.Therefore,innovative and rationally designed combined tumor immunotherapy is an effective way to improve the therapeutic effect.In the present work,ICB inhibitors were conjugated to an activated DC-derived exosome vaccine for combined cancer immunotherapy.Dendritic cell exosomes have lymph node targeting homing and can effectively enrich in lymphoid tissue,activating immune response.Thus,exosomes collected from ovalbumin(OVA)-pretreated DCs(Exo-OVA)trigger the production of anti-OVA antibodies against OVA-expressing B16 cancer cells(B16-OVA)and the activation of CD8+ T cell responses.Furthermore,to improve the efficacy of vaccine-based therapy,anti-programmed death-ligand 1 antibodies(aPD-L1)were covalently conjugated to Exo-OVA(Exo-OVA-aPD-L1)to combine the vaccine and immune checkpoint blockade therapies.Moreover,Exo-OVA could be regarded as a nanocarrier for aPD-L1 that would enhance the stability of aPD-L1 and its accumulation in tumor tissue.Thus,the combination of DC-derived vaccines with checkpoint blockade may provide a synergistic therapeutic strategy with enhanced effectiveness and decreased systemic side effects In addition,through the treatment of tumor-bearing mice of different models,it has been fully proved that the combined immunotherapy of tumor vaccine and immune checkpoint blocker can not only eliminate the primary cancer,but also effectively inhibit the tumor recurrence and metastasis.