Back to Coley: rethinking bacteria as an anticancer agent 3409

Description Bacteria engineered to express tumor antigens as a cancer vaccine have yielded mixed results. Here, we utilized an attenuated strain of Listeria monocytogenes (ΔactA, Lm) that does not express tumor antigens to explore the immunological response to Listeria itself in the context of intravenous (IV), intratumoral (IT), or a combination of IV+IT administration into tumor-bearing mice. Unexpectedly, we found that Lm persisted long-term in tumors of immune competent mice. While IT Lm alone led to the recruitment of immunosuppressive immune cells that promoted tumor growth, IV Lm followed by IT Lm controlled tumors. IV Lm vaccination generated a pool of anti-Lm cytotoxic CD8 T cells that killed Lm-infected non-tumor cells in tumors to control tumor growth. Furthermore, tumor control was completely dependent on Lm triggering of the innate Toll-like receptor 2. TLR2 stimulation in innate immune cells supported the priming of Lm-specific T cells in lymphoid tissues and their function in tumors. TLR2 also promoted tumor antigen cross-presentation by DC1s, enhancing the frequency and functionality of tumor-specific CD8 T cells. Most critically, TLR2 stimulation in innate immune cells destabilized Foxp3 expression in regulatory T cells, reducing intratumoral immunosuppression. Together, our findings reveal the potent, multifactorial immunostimulatory potential of bacteria for cancer immunotherapy, and provide a novel mechanism for treating cancer by targeting bacteria colonizing tumors. Funding Sources This research was supported by 1DP2CA247830-01 and R01CA283604 from the National Institutes of Health (NCI) and C23CR5612 from the UC CRCC Cancer Research Coordinating Committee. M.D. is a Pew-Stewart Scholar and a St. Baldrick’s Scholar with generous support from Hope with Hazel.