Abstract

Purpose: The immunosuppressive microenvironment of tumors reduces the effectiveness of immunotherapies. Apelin as an immunosuppressor peptide is expressed in the microenvironment of many tumors. Thus, inhibition of apelin-related protumor activities can promote the effectiveness of cancer immunotherapy. Here, we investigated the efficacy of a dendritic cell (DC) vaccine in combination with an apelin receptor antagonist, ML221, to modulate Th1 and Th2 cell-related responses in breast cancer-bearing mice. Materials and methods: Tumor was induced in female BALB/c mice by injecting 7 x 10(5 )4T1 cells in the right flank. Tumor-bearing mice were then given PBS, ML221, DC vaccine and "ML221 + DC vaccine " for 21 days. On day 37, mice were sacrificed and the frequency of Th1/Th2 cells in spleen and serum levels of IFN-gamma/IL-10 were determined using flow cytometry and ELISA, respectively. Lung metastasis was evaluated in lung tissues stained with hematoxylin and eosin. Finally, the obtained data were analyzed using appropriate statistical tests. Results: Combination therapy with ML221 + DC vaccination was more effective in reducing tumor growth (P < 0.0001), preventing lung metastasis (P < 0.0001) and increasing survival rate (P < 0.01) compared to the control group. Moreover, combination treatment substantially increased the frequency of Th1 cells while decreasing the frequency of Th2 cells in the spleen compared to the control group (P < 0.01). It also reduced serum levels of IL-10 compared with the control group (P < 0.05). Conclusion: Our findings showed that combination therapy using ML221 + DC vaccine can be considered as an effective cancer therapeutic program to potentiate anti-tumor immune responses.