Listeria monocytogenes, a Gram-positive facultative intracellular pathogen, is capable of stimulating robust cell-mediated immunity and is currently being developed as an immunotherapeutic platform. Attenuated L. monocytogenes has shown promise as a cancer immunotherapy in recent clinical trials; however, the mechanism of how L. monocytogenes induces a cell-mediated response remains largely unknown. Previous research suggests that L. monocytogenes must reach the host cytosol to stimulate an adaptive immune response, thus leading researchers to hypothesize that cytosolic innate immune sensing is important for the development of adaptive immunity. Unexpectedly, strains of L. monocytogenes that hyper-activate innate immune systems, such as the inflammasome, generate decreased adaptive immune responses. The overarching goal of this proposal is to understand how inflammasome activation by L. monocytogenes impairs the generation of cell-mediated immunity and to modulate these consequences for improved immunotherapeutic outcomes. We have previously shown that the inflammatory milieu downstream of inflammasome activation, which consists of IL-1?, IL-18, and eicosanoids, is largely responsible for impairing cell-mediated immune responses. This research is driven by the hypothesis that inflammasome-associated inflammation, particularly eicosanoid production, impairs cell-mediated immunity. We will characterize the inflammatory milieu downstream of inflammasome activation using Luminex technologies and ELISAs for eicosanoids. We will next modulate the presence of eicosanoids following inflammasome activation and examine generation of CD8+ T- cells in a prostate cancer tumor model to both self and non-self antigens. Additionally, we will test the impact of eicosanoid inhibition on modulating anti-tumor responses through both decreasing tumor burden and increasing the formation of tumor-infiltrating lymphocytes. Finally, we will engineer L. monocytogenes to express inflammasome inhibitors known as pyrin-only proteins (POPs), and characterize these strains in their ability to inhibit IL-1?, IL-18, and eicosanoid production. Additionally, we will test these strains for their abilities to increase cell-mediated immune responses and decrease tumor burden. Completion of this work will provide insight into how inflammasome-specific inflammation impairs cell-mediated immunity and examine novel means of inhibiting inflammasome activation. These results have implications for improving not only L. monocytogenes as an immunotherapy platform, but also other pathogen-based immunotherapeutic platforms including Salmonella typhimurium and adenovirus that have been shown to activate the inflammasome. Further, this work will extend to other vaccine platforms that induce inflammasome activation including DNA vaccines and vaccines that use the adjuvant, alum.
Cancer affects millions of people each year, and cancer immunotherapy with attenuated bacteria is a novel treatment approach. Listeria monocytogenes is one such platform that is being developed as an immunotherapy, but how L. monocytogenes generates an effective tumor response in different molecular environments is unknown. This proposal addresses how the downstream consequences of the inflammasome, one innate pathway activated by L. monocytogenes, influences the development of cell-mediated and anti- tumor immunity with the goal that we can rationally design more effective cancer immunotherapies.
| Theisen, Erin; McDougal, Courtney E; Nakanishi, Masako et al. (2018) Cyclooxygenase-1 and -2 Play Contrasting Roles in Listeria-Stimulated Immunity. J Immunol 200:3729-3738 |
| Theisen, Erin; Sauer, John-Demian (2017) Listeria monocytogenes-Induced Cell Death Inhibits the Generation of Cell-Mediated Immunity. Infect Immun 85: |
| Felley, Laura E; Sharma, Akshat; Theisen, Erin et al. (2016) Human Invariant NKT Cells Induce IL-1? Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway. J Immunol 197:2455-64 |
| Theisen, Erin; Sauer, John-Demian (2016) Listeria monocytogenes and the Inflammasome: From Cytosolic Bacteriolysis to Tumor Immunotherapy. Curr Top Microbiol Immunol 397:133-60 |
