Cellular mechanisms underlying beneficial versus detrimental effects of bacterial antitumor immunotherapy

Bacteria engineered to express tumor antigens as cancer vaccines have produced mixed results. Here, we used an attenuated strain of Listeria monocytogenes (ΔactA, Lm) that lacks tumor antigens to examine the immune response to Lm itself in tumor-bearing mice following intravenous (i.v.), intratumoral (i.t.), or combined i.v. + i.t. Lm delivery. Unexpectedly, i.t. Lm alone recruited neutrophils to tumors, which became immunosuppressive, provided an intracellular reservoir for long-term persistence of Lm in tumors, and promoted tumor growth. In contrast, prior i.v. Lm administration generated anti-Lm cytotoxic CD8⁺ T cells that infiltrated tumors upon i.t. Lm delivery. These Lm-specific CD8⁺ T cells control tumors by inducing cancer cell apoptosis, limiting cancer cell proliferation, and enhancing tumor antigen cross-presentation to tumor-specific T cells. Thus, an anti-Lm CD8⁺ T cell response against Lm-colonized tumors can control cancer, offering a paradigm for cancer immunotherapy that leverages systemic CD8⁺ T cell immunity targeting i.t. bacteria.