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Inflammasome Activation Impairs Cell-mediated Immunity to Listeria Monocytogenes

出版	University of Wisconsin--Madison, 2017
URL	http://books.google.com.hk/books?id=JvctswEACAAJ&hl=&source=gbs_api

註釋Immunotherapy, the stimulation of the immune system to generate anti-tumor responses, has been heralded as one of the most important breakthroughs in medicine. Immunotherapies include the use of checkpoint blockades, adoptive cell therapies, DNA vaccines, and attenuated pathogens that stimulate robust anti-tumor responses. Listeria monocytogenes is a Gram-positive intracellular genetically tractable pathogen capable of breaking self-tolerance that stimulates robust innate and adaptive immune responses. These properties make L. monocytogenes an ideal immunotherapeutic platform to generate tumor specific cell-mediated immune responses. Despite years of study, how robust CD8+ T-cell responses that are capable of breaking self-tolerance remains unknown. We and others have hypothesized that activation of cytosolic innate immune responses are critical for the formation of cell-mediated immunity. Surprisingly, however, we have previously shown that activation of one innate immune response, the inflammasome, is detrimental for the development of immunity. Inflammasome activation results in a Gasdermin-D dependent lytic form of cell death known as pyroptosis, release of pro-inflammatory cytokines IL-1β and IL-18, and production and secretion of lipid mediators known as eicosanoids. Here, I examine the downstream consequences of inflammasome activation to determine how each impacts the generation of immunity. We find that cell death, including inflammasome-dependent pyroptosis, as well as apoptosis and necrosis, impair immunity to L. monocytogenes. Additionally, we observe that eicosanoids downstream of cyclooxygenase (COX) activity modulate immunity to L. monocytogenes. Specifically, the constitutive enzyme COX-1 is detrimental to immunity while inducible COX-2 and prostaglandin E2 are critical for L. monocytogenes stimulated immunity. Finally, I examine novel methods of improving L. monocytogenes as an immunotherapeutic by developing a platform of L. monocytogenes to release plasmid DNA within the host cytosol to expand the antigen repertoire of L. monocytogenes immunotherapy and engineering L. monocytogenes to express novel inflammasome inhibitor proteins (pyrin-only proteins, POPs). Taken together, my results suggest that the inflammatory component of inflammasome activation, including eicosanoids, is detrimental to the generation of L. monocytogenes stimulated immunity. We suggest that development of novel inhibitors, such as POPs, and modulation of eicosanoid production through limited use of NSAIDs will be critical for success of L. monocytogenes as an immunotherapeutic platform.