Intracellular Innate Immune Receptors in Cancer Suppression and Immunotherapy

细胞内先天免疫受体在癌症抑制和免疫治疗中的作用

• 批准号: 10019472
• 负责人: Jenny P Ting
• 金额: $ 92.59万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10019472
• 关键词: Address; Advanced Malignant Neoplasm; Affect; Animals; Anti-Inflammatory Agents; Binding; Cancer Model; Cells; Chronic; Colitis; Colitis associated colorectal cancer; Colorectal Cancer; Complex; Crohn' s disease; Family; Family member; Foundations; Gene Family; Genetic; Goals; Homeostasis; Human; Immune; Immunologic Receptors; Immunotherapy; Inflammasome; Inflammation; Inflammatory Bowel Diseases; Leucine-Rich Repeat; Link; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Modeling; Molecular; Mus; Natural Immunity; Nucleotides; Obesity; Pattern; Predisposing Factor; Proteins; Recording of previous events; Resistance; Risk Factors; Role; Translating; adaptive immunity; cancer immunotherapy; cancer therapy; combat; genetic association; gut microbiome; improved; member; metaplastic cell transformation; microbial; microbiome; mouse model; novel strategies; receptor

Abstract The challenges addressed by this R35 application are multiple. First, colorectal cancer (CRC) remains a leading cancer worldwide that is resistant to many treatments. Two important risk factors for CRC are a history of chronic colitis or inflammatory bowel disease (IBD) and obesity, both of which are increasing at an alarming rate. However, the mechanisms linking these predisposing factors to CRC are not well understood and thus there is a pressing need to elucidate these basic mechanisms. Second, obesity is also a contributing factor to other gastrointestinal cancers, where the role of innate immunity receptors is less well-defined than CRC. Understanding the roles of innate immunity in these other cancers is a high priority. Third, the interaction of host genetics, microbiome, inflammation and cellular transformation is complex, but fundamental to the onset of gastrointestinal cancers. Elucidating this network of interaction is important for devising new approaches for cancer therapy. Fourth, while the roles of adaptive immune molecules and cells have been the main stake of cancer immunotherapy, much less emphasis has been placed on innate immune receptors which may alter adaptive immunity to advance cancer immunotherapy, which should be an attractive strategy to combat cancer. Finally, while studies in animals are important in establishing a foundation, a well-defined plan to translate basic findings to humans remains the ultimate goal and challenge that we will address. The NLR (nucleotide-binding domain, leucine-rich repeat containing proteins, or nucleotide-oligomerization domain receptor) is a multi-member gene family that encodes a group of cytosolic proteins that are involved in the intracellular sensing of microbial products as well as damage-associated molecular patterns. NOD2, an NLR family member, has a strong genetic association with Crohns' disease and has been implicated in colitis- associated CRC. Additionally, NLRs including NOD2 and NLRP12 can affect the microbiome to impact colitis in mice, suggesting that NLR family members are important in maintaining or disrupting the homeostasis of gut microbiome. We and others have shown a role for the inflammasome NLRs in models of colitis and CRC. In addition to our analyses of well-studied inflammasome components in models of colitis and CRC, we have been at the forefront of defining a strong role for other NLRs which have anti-inflammatory functions (referred to as inhibitory NLRs), and can alter the course of inflammation and cancer. This proposal plans to examine the roles of NLRs in humans and in murine models of cancers, to elucidate the complex interaction of NLRs with the microbiome and cellular transformation and to harness these proteins to enhance cancer immunotherapy.

抽象的 该R35应用程序所针对的挑战是多个。首先，结直肠癌（CRC）仍然是 全球领先的癌症对许多治疗具有抵抗力。 CRC的两个重要危险因素是历史 慢性结肠炎或炎症性肠病（IBD）和肥胖症，这两者都在令人震惊的 速度。但是，将这些诱发因素与CRC联系起来的机制尚不清楚，因此 迫切需要阐明这些基本机制。其次，肥胖也是一个促成因素 其他胃肠道癌，与CRC相比，先天免疫受体的作用不明确。 了解先天免疫在这些其他癌症中的作用是重中之重。第三，相互作用 宿主遗传学，微生物组，炎症和细胞转化很复杂，但对发作至关重要 胃肠道癌。阐明这种互动网络对于设计新方法很重要 癌症治疗。第四，而自适应免疫分子和细胞的作用一直是 癌症免疫疗法，更少的重点已放在可能改变的先天免疫受体上 适应性免疫以促进癌症免疫疗法，这应该是对抗的有吸引力的策略 癌症。最后，尽管对动物的研究对于建立基础很重要，但定义明确的计划 将基本发现转换为人类仍然是我们将要解决的最终目标和挑战。 NLR（核苷酸结合结构域，富含亮氨酸的重复含有蛋白质或核苷酸 - 寡聚化 域受体）是一个多成员的基因家族，它编码一组参与的胞质蛋白 微生物产物的细胞内感应以及损伤相关的分子模式。 nod2，an NLR家族成员，与克罗恩斯疾病有着牢固的遗传关联，并与结肠炎有关 相关的CRC。此外，包括NOD2和NLRP12在内的NLR会影响微生物组，以影响结肠炎 在老鼠中，暗示NLR家族成员在维持或破坏肠的体内稳态方面很重要 微生物组。我们和其他人在结肠炎和CRC模型中表现出了炎性体NLR的作用。在 除了我们对结肠炎和CRC模型中良好的炎性体成分的分析，我们有 一直处于定义具有抗炎功能的其他NLR的最前沿（引用 作为抑制性NLR），可以改变炎症和癌症的过程。该建议计划检查 NLR在人类和癌症模型中的作用，以阐明NLR的复杂相互作用 通过微生物组和细胞转化，并利用这些蛋白质来增强癌症 免疫疗法。