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Potentiation of Anti-tumor Immunity by RIPK1/RIPK3-dependent Necroptosis
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Potentiation of Anti-tumor Immunity by RIPK1/RIPK3-dependent Necroptosis. |
| 개인저자 | Snyder, Annelise G. |
| 단체저자명 | University of Washington. Immunology. |
| 발행사항 | [S.l.]: University of Washington., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 159 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-03B. Dissertation Abstract International |
| ISBN | 9781085736190 |
| 학위논문주기 | Thesis (Ph.D.)--University of Washington, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Advisor: Oberst, Andrew. |
| 이용제한사항 | This item must not be sold to any third party vendors.This item must not be added to any third party search indexes. |
| 요약 | Programmed cell death (PCD) represents a set of signaling processes evolved as a mechanism to eliminate cells, both during turnover under homeostatic conditions as well as removal of cells that have been compromised by insults such as infection or injury. Distinct cell death modalities, such as apoptosis, necroptosis, and pyroptosis, differ with respect to their signaling requirements, morphological characteristics, and molecular species produced or released by dying cells. The immune system has evolved to recognize various types of signals associated with cell death, allowing it to distinguish between physiological cell death at equilibrium and potential threats to the host such as infection. The immune system can then respond to these signals appropriately in order to either (a) dampen responses to promote immune tolerance in the context of homeostatic cellular turnover, or (b) promote inflammation that potentiates pathogen clearance in the context of infection. The mechanisms underlying the downstream immune responses mounted against dying cells have been primarily studied in settings of autoimmunity or pathogenic infection. However, characterization of these responses has been relatively poorly defined in models of tumor immunology, as these studies are complicated by the evasion of cell death signaling mechanisms commonly exhibited by transformed tumor cells.Tumor immunotherapy encompasses a repertoire of clinical treatments that aim to stimulate immune cells such that they recognize and eliminate tumor cells, and has shown remarkable efficacy in patients. Many immunotherapeutic agents function by promoting inflammatory immune responses, either by stimulating innate immune signaling pathways or by enhancing the activation and expansion of tumor-specific cytotoxic CD8+ T cells. Therefore, strategies to manipulate the immunogenicity of tumor cell death to more potently stimulate tumor-specific immunity constitutes an important target that could potentially synergize with existing immunotherapy treatments. Inflammatory forms of PCD are of particular interest in the context of tumor immunity, as the tumor microenvironment (TME) is typically viewed as a highly immunosuppressive tissue niche. Necroptosis is one such inflammatory form of PCD which occurs downstream of the receptor-interacting protein kinases RIPK1 and RIPK3. The activation of this complex leads to lytic cell death via MLKL-mediated pore formation, accompanied by de novo production of pro-inflammatory mediators such as chemokines and cytokines. Considering the potently inflammatory nature of necroptosis in comparison to other cell death modalities such as apoptosis, we sought to test how specific induction of necroptosis within the TME instructs anti-tumor immunity.In this dissertation, we show that ectopic administration of necroptotic cells to the TME promotes BATF3+ cDC1- and CD8+ leukocyte-dependent anti-tumor immunity accompanied by increased tumor antigen loading by tumor-associated antigen presenting cells. Tumor control by necroptotic cells requires the activity of the RIPK1/RIPK3 signaling complex and its subsequent activation of NF-B, but not the release of damage-associated molecular patterns (DAMPs) or their ability to stimulate innate pattern recognition receptors (PRRs), highlighting a critical role for death-independent functions of the RIPK1/RIPK3 necrosome in determining the immunogenicity of necroptotic cells. Additionally, immune stimulation by necroptotic cells synergizes with co-administration of the immune checkpoint blockade (ICB) reagent -PD-1, conferring durable tumor clearance in animals that received dual therapy. Furthermore, we report the development of constitutively-active forms of the necroptosis-inducing enzyme RIPK3, and show that delivery of a gene encoding this enzyme to tumor cells using recombinant adeno-associated viruses (AAVs) induces tumor cell necroptosis which synergizes with immune checkpoint blockade to promote durable tumor clearance. Collectively, these findings define a beneficial role for RIPK1/RIPK3 activation as a proximal target in the initiation of tumor-specific immune responses.Although monotherapy with existing immunotherapy modalities such as ICB has shown great efficacy in a subset of cancer patients, restoration of neoangiten recognition alone is often insufficient to eliminate tumors in most individuals. Therefore, successful tumor immunotherapy regimens will likely require the rational selection of multiple treatment modalities aimed at orthogonal immune targets in order to achieve optimal clinical outcomes. Based on our findings, we propose that maximizing the immunogenicity of dying cells within the tumor microenvironment through specific activation of the necroptotic pathway represents one such beneficial treatment approach that may warrant further clinical development. This work has yielded additional insights regarding the relationship between PCD modalities and anti-tumor immune responses, and provides evidence that induction of alternate death pathways such as necroptosis could improve therapeutic outcomes in the context of tumor immunity. |
| 일반주제명 | Immunology. Cellular biology. |
| 언어 | 영어 |
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