Flagellin-B-expressing Salmonella Typhimurium Improves the Efficacy of Anti-PD- 1 Therapy by Remodeling the Tumor Microenvironment in Colorectal Cancer

Abstract

Abstract Although patients with colorectal cancer (CRC) typically respond poorly to conventional chemotherapy, it remains the standard treatment. Clinical studies involving CRC patients have reported that chemotherapy promotes the infiltration of CD8+ T cells into the tumor and improves the therapeutic response to immune checkpoint inhibitors, such as those targeting programmed cell death protein 1 (PD-1). Salmonella typhimurium contributes to tumor eradication by transforming the immunosuppressive tumor microenvironment (TME) into an immunogenic one, which improves the antitumor immune response; however, the combined effect of S. typhimurium therapy and PD-1 blockade on the TME is not well understood. Here, we investigated the anticancer effects of a combination therapy comprising an attenuated S. typhimurium strain engineered to secrete Vibrio vulnificus flagellin B (S.ΔppGpp FlaB) and an anti-PD-1 antibody. We found that S.ΔppGpp FlaB significantly promoted the infiltration of immune cells, including M1 macrophages, dendritic cells, and CD8+ T cells, into the tumor, while increasing tumor PD-1 and PD-L1 expression via the AKT/PI3K pathway. Moreover, our encouraging results in tumor-bearing mouse models suggest that combining S.ΔppGpp FlaB with PD-1 blockade could be a promising strategy for enhancing the efficiency of anti-PD-1 therapy in patients with CRC.