The primary goal of tumor immunotherapy is the generation of a robust cell mediated immune response. Though the mechanism remains unclear, immunization with the intracellular bacterial pathogen Listeria monocytogenes results in the induction of robust cell mediated immunity. In addition to being a promising immunotherapeutic platform, L. monocytogenes represents an ideal model system for understanding how cell mediated immune responses are generated. We have previously demonstrated that activation of the inflammasome by cytosolic L. monocytogenes inhibits the generation of cell mediated immunity. The goal of this proposal is to understand the mechanism behind this observation and to identify opportunities for therapeutic intervention, including inhibition of L. monocytogenes induced inflammasome activation. We will achieve this through the following specific aims: 1) Determine if cell death (pyroptosis, apoptosis, and/or necrosis) modulates the development of tumor specific cell mediated immunity following L. monocytogenes immunization 2) Identify inflammasome dependent alterations in inflammation that influence the development of cell mediated immunity following L. monocytogenes immunization 3) Inhibit inflammasome activation during L. monocytogenes immunization to increase the development of cell mediated immunity We will use a unique set of L. monocytogenes strains engineered to specifically activate different cell death pathways to understand how pyroptosis, apoptosis and necrosis influence the generation of tumor specific cell mediated immunity in the context of infection. Specifically we will characterize antigen specific T-cells, therapeutic and prophylactic tumor regression models and finally dendritic cell antigen presentation to understand how cell death modulates the immune response. Subsequently, we will use a combination of transgenic mice and inhibitors to define the role of cytokines (eg IL10), eicosanoids (eg PGE2) T-cell activation markers in the generation of inflammasome influenced cell mediated immune responses. Finally, we will engineer L. monocytogenes to express viral and/or mammalian inhibitors of inflammasome activation, to test the hypothesis that inflammasome inhibition will lead to more robust antigen specific T-cell development and anti-tumor immunity. These studies will directly contribute to the generation of better immunotherapies in two ways. Our results will identify the negative role of the inflammasome in generation of cell mediated immunity and suggest opportunities for therapeutic intervention. This is important not only for L. monocytogenes based immunotherapies but for other vaccines and therapeutics that result in inflammasome activation including the adjuvant alum and DNA vaccines. These studies will also directly lead to the development of a more robust L. monocytogenes based immunotherapeutic platform through the design of strains that actively inhibit inflammasome activation.
The goal of cancer immunotherapy is the generation of tumor specific cell mediated immunity that results in the killing of tumor cells while leaving healthy neighboring cells intact. Attenuated strains of Listeria monocytogenes that express tumor antigens have shown great promise as immunotherapeutic platforms. The goal of this proposal is to understand the mechanism by which L. monocytogenes triggers immunity and to generate strains that induce more robust responses through the modulation of the innate immune response to the bacterium.
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