Silencing of suppressor of cytokine signaling 1 enhances the immunological effect of mucin 1-calreticulin-primed 4T1 cell-treated dendritic cells in breast cancer treatment.

Abstract

In cancer immunotherapy, dendritic cell (DC)-based vaccines represent a promising, yet challenging, treatment method. In addition to overcoming the low expression levels of antigenic epitopes on cancer cells, it is also necessary to overcome the inhibitory effect of suppressor of cytokine signaling 1 (SOCS1) on DC self-antigen presentation. Our group previously demonstrated that calreticulin (CRT) translocated type I transmembrane glycoprotein mucin 1 (MUC1), a breast cancer antigen, to the surface of 4T1 cells, and that treatment with MUC1-CRT-primed 4T1 cell-treated DCs induced apoptosis in a breast cancer cell line. In the present study, cell penetrate peptide, hpp10-DRBD was successfully used to deliver siRNAs into bone marrow-derived (BM) DCs to construct SOCS1-silenced DCs, which were incubated with MUC1-CRT-primed 4T1 cells, and antigen-specific antitumor immunity was markedly enhanced in vitro and in vivo. These results demonstrated that SOCS1-silencing, combined with MUC1-CRT-primed 4T1 cell treatment, may induce increased cytokine production and T cell proliferation by DCs. Furthermore, the in vivo experimental data demonstrated that the silencing of SOCS1 combined with MUC1-CRT-primed 4T1 treatment of BMDCs may induce enhanced immunological effects. The results of the present study have implications for the development of more effective DC-based tumor vaccines, suggesting that the combination of high tumor-associated antigen expression levels on cancer cells with the silencing of a critical inhibitor of DC antigen presentation may be beneficial.