Recombinant Listeria promotes tumor rejection by CD8 + T cell-dependent remodeling of the tumor microenvironment.

Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1 ⁺ PD1 ^lo CD62L ^- CD8 ⁺ T cells. These IFNγ-producing effector CD8 ⁺ T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS) ⁺ CD206 ^- M1 phenotype. Remarkably, these LADD-Ag-induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8 ⁺ T cells.
Competing Interests: Conflict of interest statement: W.D., V.L., T.E.H., E.E.L., W.G.H., R.F., G.B., G.E.K., A.L.D., P.L., M.L.L., and T.W.D. are current or former paid employees of Aduro Biotech, and hold stock in the company. D.A.P. was supported by National Institutes of Health Grants 1P01 AI063302 and 1R01 AI027655 and a Grant from Aduro Biotech (IVRI). D.A.P. has a consulting relationship with and a financial interest in Aduro Biotech, and both he and the company stand to benefit from the commercialization of the results of this research.
(Copyright © 2018 the Author(s). Published by PNAS.)