Chemokines expressed by engineered bacteria recruit and orchestrate antitumor immunity
Thomas Savage, Rosa L. Vincent, Sarah S. Rae, Lei Huang, Alexander Ahn, Kelly Pu, Fangda Li, Kenia de los Santos-Alexis, Courtney Coker, Tal Danino, Nicholas Arpaia
Abstract
Tumors use multiple mechanisms to actively exclude immune cells involved in antitumor immunity. Strategies to overcome these exclusion signals 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 of therapeutic candidates previously unavailable using conventional systemic administration techniques. Here, we engineer bacteria to intratumorally release chemokines to attract adaptive immune cells into the tumor environment. Bacteria expressing an activating mutant of the human chemokine CXCL16 (hCXCL16 K42A ) offer therapeutic benefit in multiple mouse tumor models, an effect mediated via recruitment of CD8 + T cells. Furthermore, we target the presentation of tumor-derived antigens by dendritic cells, using a second engineered bacterial strain expressing CCL20. This led to type 1 conventional dendritic cell recruitment and synergized with hCXCL16 K42A -induced T cell recruitment to provide additional therapeutic benefit. In summary, we engineer bacteria to recruit and activate innate and adaptive antitumor immune responses, offering a new cancer immunotherapy strategy.