Engineered bacteria recruit and orchestrate anti-tumor immunity

Abstract

Tumors employ multiple mechanisms to actively exclude or suppress adaptive immune cells involved in anti-tumor immunity. Strategies focused on overcoming these immunosuppressive or exclusion signals - through localized delivery of chemokines that directly recruit immune cells into the tumor microenvironment - remain limited due to an inability to target therapeutics specifically to the tumor. Synthetic biology enables engineering of cells and microbes for tumor localized delivery, offering therapeutic candidates previously unavailable using conventional systemic administration techniques. Here, we engineer bacteria to produce and intratumorally release chemokines to attract adaptive immune cells into the tumor environment. Intravenous or intratumoral delivery of bacteria expressing an activating mutant of the human chemokine CXCL16 (hCXCL16K42A) leads to the recruitment of activated T cells within tumors and offers therapeutic benefit in multiple mouse tumor models. Furthermore, we rationally target an additional step in the immune activation cascade - specifically, the presentation of tumor-derived antigens by dendritic cells - using a second engineered bacterial strain expressing CCL20. This combined targeting approach led to the recruitment of type 1 conventional dendritic cells and effectively synergized with hCXCL16K42A-induced T cell recruitment to provide additional therapeutic benefit. In summary, we engineer bacteria to cooperatively recruit and activate both innate and adaptive anti-tumor immune responses, offering a new cancer immunotherapy strategy.