Dexamethasone augments the efficacy of attenuated Salmonella typhimurium-based cancer immunotherapy by modulating the infiltration of neutrophils and macrophages in the tumor microenvironment

Abstract:

Bacterium-mediated cancer immunotherapy (BCI) presents numerous advantages in cancer treatment, while the immune response mechanism of dexamethasone (DEX) combined with BCI for tumor treatment remains unclear. [Objective] To investigate the therapeutic efficacy and mechanism of dexamethasone in combination with attenuated Salmonella typhimurium St.ΔppGpp-mediated BCI. [Methods] The inhibitory effects of St.ΔppGpp+DEX on cancer were evaluated in a murine model of colorectal cancer. In vivo imaging was utilized to determine the tumor targeting and colonization duration of St.ΔppGpp. Organ toxicity resulted from St.ΔppGpp+DEX treatment was assessed by hematoxylin and eosin (H&E) staining. Macrophage polarization, neutrophil recruitment, and T-cell responses were analyzed by flow cytometry and immunofluorescence assay of sections. The changes in inflammatory cytokines in the tumor microenvironment were examined via qRT-PCR. A mouse model transplanted with human colorectal cancer was employed to confirm the effect of T cell depletion on the therapeutic efficacy of St.ΔppGpp+DEX. [Results] The combined treatment St.ΔppGpp+DEX significantly decreased tumor size and enhanced the survival rate of mice. DEX extended the colonization of St.ΔppGpp in tumor cells. Furthermore, St.ΔppGpp+DEX did not induce damage to vital immune organs, and it facilitated the polarization of macrophages from M2 to M1 phenotype while suppressing neutrophil recruitment. T cell depletion did not influence the efficacy of St.ΔppGpp+DEX. [Conclusion] DEX can enhance the anti-tumor effects of St.ΔppGpp by inhibiting neutrophil recruitment and increasing the proportion of M1 macrophages in the tumor microenvironment.