Cellular mechanisms underlying beneficial versus detrimental effects of bacterial antitumor immunotherapy

Summary 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 antigen 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 in tumors of immune competent mice, regardless of the administration route. While IT Lm alone led to the recruitment of immunosuppressive immune cells that promoted tumor growth, IV Lm followed by IT Lm controlled tumor growth. IV Lm vaccination generated a pool of anti- Lm cytotoxic CD8 T cells that killed Lm -infected non-tumor cells to control tumor growth both indirectly, by limiting cancer cell proliferation, and directly, by enhancing tumor-specific T cell responses. Our findings reveal a differential impact of IT Lm administration on tumor progression that depends on the presence of anti- Lm CD8 T cells, which alone are sufficient to promote therapeutic efficacy.