Combined Therapy with Dendritic Cell Loaded-Exosomes Supplemented with PD-1 Inhibition Have Superior Antitumor Effect in Hepatocellular Carcinoma

Abstract Background Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths and has low sensitivity to conventional therapies. Dendritic cell (DC) loaded tumor-exosomes (TEX) have shown antitumor effects in a murine HCC model. However, the combined antitumor efftcts of DC-TEX and programmed death protein 1 antibody (PD-1 Ab) at different time application has not been investigated. Methods In this study, ectopic, orthotopic, and diethylnitrosamine (DENA)-induced HCC models were established and treated with DC-TEX alone or in combination with PD-1 Ab at different time points. Meanwhile, we established an orthotopic HCC model in BALB/C nude mice and restore t cells. Results The results showed that along with the increased number of CD8+ T cells, the PD-1+CD8+ T-cell population was also significantly increased after DC-TEX injection. The number of CD8+ T cells peaked 72 h after DC-TEX injection, and the PD-1+CD8+ T cells also showed a similar result. Subsequently, the PD-1 Ab was applied in combination with DC-TEX at a series of time points (0, 24,72, 96, 120 or 168 h). Surprisingly, the combined treatment showed strong antitumor effects and this effect was most prominent when PD-1 Ab was administerd at 72 h. In vitro, PD-1 Ab also significantly reversed the proliferative ability of PD-1+CD8+ T cells at 72 h. The combined antitumor effects of PD-1 Ab and DC-TEX were mainly through their stimulation on CD8+T cells proliferation as well as repression for T cell exhaustion. Conclusion In conclusion, the combination of DC-TEX and PD-1 Ab significantly suppresses tumor growth in a murine HCC model and that the antitumor effect is affected by the timing of PD-1 Ab treatment.