Effect of genetically engineered <i>Salmonella typhimurium</i> secreting conantokin G on PD-L1 antibody therapy and tumor regression in colorectal cancer.

Abstract

e14566 Background: Engineered attenuated Salmonella represents an intensive strategy for targeting tumors, which enhances the effectiveness of combination therapies involving immune checkpoint inhibitors (ICIs). Conantokin G is a N-methyl-D-aspartate receptor (NMDAR) antagonist that is highly expressed in various cancers; however, direct evaluation of the anticancer efficacy of conantokin G is scarce. Methods: We established a Salmonella typhimurium strain engineered to deliver and secrete conantokin G and evaluated its anticancer efficacy in vitro and in vivo . In vitro experiments were performed using colorectal cancer cell lines and three-dimensional culture models to assess cell growth and death. Additionally, in vivo experiments were performed in BALB/c mice to evaluate the safety and anticancer efficacy of the strain secreting conantokin G as well as its combined treatment with immune checkpoint inhibitors. Results: The engineered Salmonella strain producing conantokin G demonstrated secretion capability, tumor-targeting ability, and safety. This strain inhibited colorectal cancer cell growth and induced cell death in both in vitro and in vivo models, leading to tumor regression. The increased expression of PD-L1 induced by attenuated Salmonella facilitated the application of combination therapy with anti-PD-L1 antibodies, significantly reducing tumor growth along with the anti-cancer effects of conantokin G. Consistent with these findings, an analysis of 106 patients with colorectal cancer revealed that high NMDAR expression was associated with advanced T and N stages and poorer disease-free survival. Conclusions: These findings suggest the role of NMDAR as a prognostic marker and support the anticancer efficacy of conantokin G, a potent NMDAR antagonist. In summary, our findings suggest that by leveraging a targeted delivery system, conantokin G can be specifically directed to tumors to elicit anticancer effects. Thus, it may serve as a novel adjuvant agent in cancer therapy, augmenting the effects of combination treatments with additional immune-inducing effects.