Engineered live attenuated bacteria producing 5-hydroxyindole remodels heterogeneous tumor microenvironment and promotes antitumor immunity

Abstract The highly immunosuppressive tumor microenvironment (TME) stimulates cancer cells resistance to immunotherapy. We have previously shown that a live-attenuated Brucella melitensisΔ vjbR(BmΔ vjbR) bacterial strain, breaks cell immunotherapy by remodeling the TME and facilitating infiltration of cytotoxic CD8 +T (CTLs) into tumor. As result, there was shrinkage size significant improvement in survival these mice. However, BmΔ vjbRwas efficient only controlling colorectal tumors, but rendered ineffective B16 melanoma. In this study, we sought improve efficacy vjbRin different cancers engineering it augment production 5-hydroxyindole (HI), i.e., vjbR-HI. effect vjbR-HI modulating function activity CTLs assessed flowcytometry vitroassays. also intravenous injection bacteria followed adoptive CTL therapy colon carcinoma, melanoma pancreatic orthotropic murine tumors. found increased inflammatory cytokines cells. granzyme-B cytotoxicity enhanced on treatment with bacteria. remodeled ameliorated MC32-CEA cancer, B16-OVA Panc-02 Moreover, homed uptake myeloid derived suppressor Overall, our findings demonstrate remodels heterogeneous TMEs promote CTL-mediated antitumor immunity. These translational potential microbial Jugal Das Jianxun Song are recipients Careers Immunology Fellowship 2022.