Depletion of Polymorphonuclear Myeloid-Derived Suppressor Cells Increases Efficacy of Listeria monocytogenes Cancer Vaccine

Abstract The tumor microenvironment is highly immunosuppressive, allowing cancer to evade the immune system by inducing the dysfunction, exhaustion, or subversion of CD8+ T-cell functions. Cancer immunotherapies using attenuated strains of Listeria monocytogenes (Listeria) engineered to express tumor antigens have been demonstrated to promote cancer antigen-specific CD8+ T-cells that infiltrate the tumor microenvironment and control mouse models of cancer. However, in human clinical trials, initial IV therapies utilizing Listeria did not demonstrate strong clinical efficacy, suggesting that the generation of tumor-specific CD8+ T-cells recognizing tumor antigens alone is insufficient to provide robust tumor control. Here, we demonstrate that intratumoral (IT) or intravenous (IV) inoculation of an attenuated form of Listeria(ΔActA) demonstrated no therapeutic benefit in the context of establish MC38 tumor-bearing mice while predominantly recruiting and infecting CD11b+Ly6G+CD14+ cells in the tumor microenvironment, markers associated with polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). In vitro analysis of PMN-MDSC infection by Listeria revealed increased immunosuppressive function, indicating a possible adverse outcome of Listeria treatment in vivo. Further, IV or IT injection of Listeria in the context of PMN-MDSC depletion increased the therapeutic efficacy of Listeria therapy and promoted a robust CD8+ T-cell mediated anti-tumor response. Collectively, our results demonstrate that depletion of PMN-MDSCs may be required to mediate the therapeutic efficacy of Listeria inoculation in the context of cancer immunotherapy and the production of an effective anti-tumor immune response. Supported by grants from NIH (DP2CA247830) & Cancer Research Coordinating Committee (CRCC) (C23CR5612)