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: 10217045
• 负责人: Jenny P Ting
• 金额: $ 92.43万
• 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/10217045
• 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; 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 homeostasis; 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.

摘要 此R35应用程序解决的挑战是多方面的。首先，结肠直肠癌（CRC）仍然是一个 导致世界范围内的癌症，对许多治疗都有抗药性。CRC的两个重要风险因素是病史 慢性结肠炎或炎症性肠病（IBD）和肥胖，这两种疾病都在以惊人的速度增加。 率然而，将这些诱发因素与CRC联系起来的机制尚未得到很好的理解，因此， 迫切需要阐明这些基本机制。其次，肥胖也是一个因素， 其他胃肠道癌症，先天免疫受体的作用不如CRC明确。 了解先天免疫在这些其他癌症中的作用是一个高度优先事项。第三，互动 宿主遗传学、微生物组、炎症和细胞转化是复杂的，但却是发病的基础。 胃肠道癌症。阐明这种相互作用网络对于设计新的方法， 癌症治疗。第四，虽然适应性免疫分子和细胞的作用一直是免疫系统的主要利害关系， 癌症免疫治疗，少得多的重点放在先天免疫受体，这可能会改变 适应性免疫，以推进癌症免疫治疗，这应该是一个有吸引力的战略，以打击 癌最后，虽然动物研究对建立基础很重要，但一个明确的计划， 将基本发现转化为人类仍然是我们要解决的最终目标和挑战。 NLR（核苷酸结合结构域，富含亮氨酸重复的蛋白质，或核苷酸寡聚化） 结构域受体）是一个多成员基因家族，其编码一组胞质蛋白， 微生物产物的细胞内传感以及损伤相关的分子模式。NOD2， NLR家族成员，与克罗恩病有很强的遗传关联，并与结肠炎有关- 相关CRC。此外，包括NOD 2和NLRP 12在内的NLR可以影响微生物组，从而影响结肠炎 在小鼠中，表明NLR家族成员在维持或破坏肠道内稳态方面很重要， 微生物组我们和其他人已经显示了炎性小体NLR在结肠炎和CRC模型中的作用。在 除了我们对结肠炎和结直肠癌模型中充分研究的炎性小体成分的分析外，我们还 在确定具有抗炎功能的其他NLR的强大作用方面处于最前沿（参考文献10.1.1）。 作为抑制性NLR），并可改变炎症和癌症的进程。该提案计划审查 NLR在人类和小鼠癌症模型中的作用，以阐明NLR的复杂相互作用 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。