Discipline: Biological Sciences
Room: Exhibit Hall
Jacob Williams - University of California, Berkeley
Co-Author(s): Jesse Garcia Castillo, University of California, Berkeley, Berkeley, CA; Sebastian Fernandez, University of California, Berkeley, Berkeley, CA; Daniel Portnoy Ph.D., University of California, Berkeley, Berkeley, CA; Michel DuPage Ph.D., University of California, Berkeley, Berkeley, CA;
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. However, the pathogenesis, localization, and impacts of Listeria on the tumor microenvironment and landscape of immune cells are poorly understood, but may be harnessed to promote enhanced anti-tumor T-cell responses. Here, we demonstrate that intratumoral (IT) or intravenous (IV) inoculation of an attenuated form of Listeria(ΔActA) predominantly recruits and infects CD11b+Ly6G+CD14+ cells in the tumor microenvironment, markers associated with polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Infection of these cells established an inhibitory niche that delayed the clearance of Listeria in tumors beyond 15 days post-infection, while bacteria were cleared from the liver and spleen of tumor-bearing mice within five days. Furthermore, we observed no therapeutic benefit of IT or IV injection of non-cancer antigen expressing Listeria in the context of established MC38 tumor-bearing mice. In vitro analysis of PMN-MDSC infection by Listeria revealed increased activation and immunosuppressive function of PMN-MDSCs, 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.
Funder Acknowledgement(s): Funders of the research project include the NIH/NCI and the CRCC (Cancer Research Coordinating Committee)
Faculty Advisor: Michel DuPage, firstname.lastname@example.org
Role: Following the preliminary results of IV or IT inoculation of Listeria leading to the increased recruitment of PMN-MDSCs and the establishment of an inhibitory niche that delayed clearance beyond 15 days, for which I was involved predominantly in the takedown and processing of tissues from tumor-bearing mice and analysis of data by flow cytometry/collection of CFUs, I generated the in-vitro assay to characterize PMN-MDSC infection by Listeria and carried out the depletion and processing step of the subsequent in-vivo experiment involving IV+IT inoculation of Listeria in the context of PMN-MDSC depletion.