Intracellular Innate Immune Receptors in Cancer Suppression and Immunotherapy

摘要 该 R35 应用解决了多重挑战。首先，结直肠癌（CRC）仍然是一种 全球领先的癌症，对许多治疗方法具有耐药性。 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) 和肥胖症的发病率均以惊人的速度增加 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，肥胖也是一个影响因素 其他胃肠道癌症，其中先天免疫受体的作用不如结直肠癌明确。 了解先天免疫在这些其他癌症中的作用是当务之急。三、互动 宿主遗传学、微生物组、炎症和细胞转化很复杂，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方法非常重要 癌症治疗。第四，虽然适应性免疫分子和细胞的作用一直是 癌症免疫疗法，较少强调先天免疫受体，这可能会改变 适应性免疫促进癌症免疫治疗，这应该是一种有吸引力的对抗策略 癌症。最后，虽然动物研究对于建立基础很重要，但明确的计划 将基本发现转化为人类仍然是我们将要解决的最终目标和挑战。 NLR（核苷酸结合域、富含亮氨酸的重复序列的蛋白质，或核苷酸寡聚化 结构域受体）是一个多成员基因家族，编码一组参与 微生物产物的细胞内传感以及与损伤相关的分子模式。 NOD2，一个 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 相关的CRC。此外，包括 NOD2 和 NLRP12 在内的 NLR 可以影响微生物组，进而影响结肠炎 在小鼠中，表明 NLR 家族成员对于维持或破坏肠道稳态很重要 微生物组。我们和其他人已经证明了炎症小体 NLR 在结肠炎和结直肠癌模型中的作用。在 除了我们对结肠炎和结直肠癌模型中经过充分研究的炎性体成分进行分析之外，我们还 一直处于定义其他具有抗炎功能的 NLR 的强大作用的最前沿（参考 作为抑制性 NLR），并且可以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 与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。

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.