Attenuated Salmonella-delivered PD-1 siRNA enhances the antitumor effects of EZH2 inhibitors in colorectal cancer

Abstract

Immunotherapy has made significant progress in the treatment of malignant tumors. However, strategies to combine immunotherapy with anticancer drugs have attracted great attention due to the low response rate and unique toxicity profile of immunotherapies and the subsequent development of acquired resistance in some initial responders. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex,is highly expressed in a variety of tumors, and targeting EZH2 has become a new strategy for tumor therapy and drug combination. Here，we studied the effect of EZH2 inhibitors on colorectal cancer cells and their combination with immunotherapy. Our results demonstrated that EZH2 inhibitors can not only significantly inhibit the survival of colorectal cancer (CRC) cells and induce apoptosis, effectively inhibit cell invasion and migration, but also cause an increase in the expression of PD-L1 receptors on the cell surface. To determine the effect of EZH2 in combination with immunotherapy, we combine EZH2 inhibitors with PD-1 siRNA delivered by attenuated Salmonella. The vivo experiments have shown that the combination of EZH2 inhibitors and Salmonella-delivered PD-1 siRNA can further inhibit the development of CRC, trigger effective anti-tumor immunity, and improve therapeutic efficacy. Its underlying mechanisms mainly involve synergistic immunomodulation and apoptosis. This study suggests an emerging strategy based on a combination of EZH2 inhibitor and immunotherapy based on PD-1 inhibition.