Neuro-immune modulation of pain in health and disease

项目总结： 大多数晚期癌症患者经历中度到重度疼痛，超过一半 在所有癌症患者中，报告说目前可用的治疗方法不足以缓解疼痛。头部和颈部 鳞状细胞癌(HNSCC)侵犯口腔和/或口咽部被认为是一种特殊的 疼痛的癌症类型，产生一致的功能障碍，导致进食困难， 吞咽，和交流。这些功能障碍大大降低了癌症患者的生活质量。 并与发病率和死亡率的增加有关。因此，对小说的需求非常迫切。 能够提供安全有效的止痛的治疗方法。此外，任何新出现的痛苦 治疗必须与现有的和新兴的癌症治疗标准相适应，例如癌症 在过去的几年里，免疫疗法已经成为许多癌症亚型的黄金标准疗法 十年。我们最近发现，感受疼痛的外周感觉神经元(伤害性感受器)表达先天的 免疫调节剂刺痛。引人注目的是，激活刺痛可以在小鼠和非人类身上产生抗伤害性感觉 处于稳定状态和病理性疼痛状态的灵长类动物。值得注意的是，作为小分子 STING激动剂在促进抗肿瘤免疫方面显示出显著的效果，目前正在 在临床试验中作为癌症治疗药物进行了探索。这项提案的目标是识别蜂窝和 STING在稳态和HNSCC中调节伤害性感受的分子机制 疼痛模型。我们假设，刺痛在稳态和疾病中动态调节伤害性感受。 依赖于伤害性感受器-免疫细胞信号及其亚细胞的机制 本地化。在特定的目标1中，我们将确定外周感觉神经元中的STING信号，TRPV1+ 伤害性感受器和经典的1型树突状细胞(CDC1s)各自参与刺痛介导的抗伤害性感觉 健康和疾病，使用同基因癌症疼痛模型，条件遗传学，行为表型， 免疫分析、生化和免疫组织化学方法。在具体目标2中，我们将确定 刺激物的亚细胞定位如何影响其分子和生理特性 伤害性和抗肿瘤免疫。总体而言，完成这些实验将证实斯汀是一种 独一无二的“神经免疫疗法”靶标，可提供组合止痛和抗肿瘤特性， 考虑到患者可供选择的选择很少，这一发现具有直接的翻译相关性 癌痛。

Project Summary: The majority of patients with advanced stage cancers experience moderate to severe pain, and more than half of all cancer patients report insufficient pain relief by the currently available therapeutics. Head and neck squamous cell carcinomas (HNSCC) involving the oral cavity and/or oropharynx are regarded as a particularly painful cancer type which produces coincident functional impairments that lead to difficulties in feeding, swallowing, and communication. These functional impairments substantially reduce quality of life for cancer patients and are associated with increased morbidity and mortality. Thus, there is a critical need for novel therapeutics that are capable of providing safe and effective pain relief. Moreover, any newly emerging pain therapeutic must be compatible with existing and emerging standard of care cancer treatments, such as cancer immunotherapy, which has emerged as the gold-standard treatment for many cancer subtypes over the last decade. We recently discovered that pain-sensing peripheral sensory neurons (nociceptors) express the innate immune regulator STING. Strikingly, activation of STING can produce antinociception in mice and non-human primates, both in steady-state conditions and in pathological pain states. This is noteworthy, as small molecule STING agonists have shown remarkable efficacy in promoting antitumor immunity and are currently being explored as cancer therapeutics in clinical trials. The objective of this proposal is to identify the cellular and molecular mechanisms by which STING regulates nociception, both in steady-state conditions and in HNSCC pain models. We hypothesize that STING dynamically regulates nociception in steady-state and disease conditions through a mechanism dependent on nociceptor-immune cell signaling and its subcellular localization. In Specific Aim 1, we will determine how STING signaling in peripheral sensory neurons, TRPV1+ nociceptors, and classical type-1 dendritic cells (cDC1s) each contribute to STING-mediated antinociception in health and disease, using syngeneic cancer pain models, conditional genetics, behavioral phenotyping, immune profiling, and biochemical and immunohistochemical approaches. In Specific Aim 2, we will determine how the subcellular localization of STING influences its molecular and physiological properties to influence nociception and antitumor immunity. Overall, completion of these experiments will substantiate STING as a unique “neuro-immunotherapy” target capable of conferring combinatorial analgesia and antitumor properties, a finding of immediate translational relevance given the paucity of options available to patients suffering from cancer pain.