Personalized tumor antigen-pulsed dendritic cell therapy synergizes with simultaneous blockade of PD-1/TIM-3 to treat lung cancer

Abstract Background Immunotherapy has become a promising innovation in human cancer treatment. However, only a minority of patients were benefited from immunotherapy, including PD-1/PD-L1 blockade, dendritic cell vaccine. Why these novel therapies failed and how to improve their therapeutic efficacy in cancer patients, particularly those with lung cancers, remain elusive. Methods The function of dendritic cells (DCs) was analyzed by various ex vivo and in vivo assays. Bone marrow were exploited in vitro to drive DCs to load whole tumor antigens (thereafter named Ag-DC) for T cell priming in vitro and in vivo. In both syngeneic and endogenous lung tumor models, the therapeutic effect, underlying mechanisms and acquired resistance of Ag-DC therapy were examined. Finally, the safety and efficacy of combination therapy of Ag-DC and simultaneous blockade of PD-1 and TIM-3 were investigated. Results The function of DCs is repressed with respect to phagocytosis of tumor cells and antigen-dependent T cell priming in lung tumor microenvironment. DCs derived from bone marrow in vitro are able to stimulate tumor antigen-specific T cell activation and subsequent killing of tumor cells. Local or systemic administration of whole tumor antigen-pulsed DCs (Ag-DCs) elicits potent T cell activation, enriched tumor-infiltrating lymphocytes, and increased memory T cells, contributing to fewer and smaller lung tumors. In addition, Ag-DC therapy induces expression of immune checkpoint molecules PD-1 and TIM-3 on T cells, which rationalizes the great synergistic efficacy of combination therapy of Ag-DC and simultaneous blockade of PD-1 and TIM-3. Conclusions These findings suggest that bone marrow derived DCs in vitro loaded with whole tumor antigens can inhibit lung tumor initiation and progression by triggering strong T-cell antitumor activity, pulmonary recruitment, and tumor infiltration. Simultaneous blockade of PD-1 and TIM-3 synergizes with Ag-DC therapy in lung cancer treatment, representing a novel combination therapy for lung cancer.