Project 1: Inhibition of Complement C5aR1 Radioprotects Normal Tissue and Radiosensitizes Tumors

项目 1：抑制补体 C5aR1 辐射保护正常组织并使肿瘤辐射增敏

• 批准号: 10707880
• 负责人: Amato J. Giaccia
• 金额: $ 22.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707880
• 关键词: Animal Model; Apoptosis; Attenuated; Cancer Model; Cell Culture Techniques; Cell Survival; Cells; Clinic; Collaborations; Colorectal Cancer; Colorectal Neoplasms; Complement; Complement Receptor; Data; Dependence; Disease; Ensure; Epithelium; Exhibits; Gastrointestinal tract structure; Genetic; Histologic; Immune; Immunity; In Vitro; Interleukin-10; Intestines; Lung; Macrophage; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Mus; Natural Immunity; Normal tissue morphology; Pathway interactions; Phosphorylation; Population; Process; Proto-Oncogene Proteins c-akt; Radiation; Radiation Protection; Radiation induced damage; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Role; Salivary Glands; Schedule; Signal Transduction; Site; Small Intestines; Stress; TP53 gene; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Tumor Promotion; Tumor Tissue; angiogenesis; antagonist; cell killing; clinical effect; colon cancer cell line; complement pathway; complement system; crypt cell; data sharing; dosimetry; effectiveness evaluation; gastrointestinal; gastrointestinal epithelium; gastrointestinal system; improved; in vivo; inhibitor; intestinal injury; irradiation; molecular targeted therapies; neoplastic cell; pharmacologic; radiation response; radioprotected; recruit; response; targeted treatment; tumor; tumor progression

Abstract (Project 1 - Oxford) Increasing the therapeutic window of radiotherapy may be achieved by using targeted therapies against cancer- associated pathways. The complement system is an innate immunity pathway, with emerging roles in cancer progression. No study has evaluated the effect of complement inhibition on both tumor and normal tissue radiation response. Here we show that targeting complement receptor C5aR1 improves radiation response in colorectal cancer models while reducing radiation-induced toxicity. Targeting C5aR1 increases IL-10 secretion, which attenuates NF-κB signaling and enhances apoptosis in tumor cells. IL-10-dependent apoptosis is observed both in vivo and in vitro suggesting a non-canonical stress-specific and likely immune-independent role for C5aR1 in regulating apoptosis. Importantly, we find that C5aR1 depletion results in decreased small intestinal histologic damage, crypt cell apoptosis and increased survival of mice following irradiation. In the small intestine, C5aR1 depletion results in increased IL-10 expression in both non-immune and immune cell populations. IL-10 signaling in CX3CR1+ macrophages is important for intestinal injury defense and C5aR1-/- mice have significantly higher levels of CX3CR1+ macrophages than WT mice. In response to irradiation, C5aR1 depletion does not attenuate NF-κB signaling but instead increases AKT activation correlating with decreased apoptosis occurring in an IL-10-depedent manner. Our data, therefore, indicate that genetically or pharmacologically targeting C5aR1 can improve radiation response in colorectal tumor models while reducing radiation-induced small bowel toxicity. Together, these findings suggest that inhibiting complement could be a promising approach to increasing the therapeutic window of radiotherapy. In this Project, we propose four specific aims to better understand the role of C5aR1 in radioprotection and radiosensitization. Aim 1 will determine the broad versus specific protection of normal epithelium (intestines, salivary glands, and lung epithelium) by C5aR1-/- mice in response fractionated and hypofractionated radiotherapy, in collaboration with Projects 2, 3, 4 and Core B. In Aim 2, we will investigate the mechanistic basis of radioprotection when C5aR1 is inhibited. Our preliminary data indicates that this is an IL-10 dependent mechanism and involves recruitment of CX3CR1+ macrophages that promote survival and angiogenesis. Aim 3 will determine how C5aR1 promotes tumor cell killing in combination with radiotherapy. The hypothesis based on our preliminary data is that C5aR1 inhibition increases IL-10 secretion, which attenuates NF-κB signaling, resulting in IL-10 dependent tumor cell killing both in cell culture and in animal models. Aim 4 will determine the effect of clinical grade C5aR1 inhibitors on radioprotecting intestine, salivary glands and lungs, and sensitizing colorectal tumors to radiotherapy. I intend to return to Stanford on a monthly or bimonthly schedule and will share this data with my colleagues at Stanford. At Oxford, we perform our own dosimetry and will cooperate with Core B at Stanford to ensure comparability of methods.

摘要（项目1 -Oxford） 通过使用针对癌症的靶向疗法来增加放射治疗的治疗窗口 相关途径。 进展。 辐射反应。 结直肠癌模型同时减少辐射诱导的毒性。 这会减弱NF-κB信号传导并增强肿瘤细胞中的apoptostostostos。 在体内和体外观察到非典型应力特异性和可能的​​免疫rolee 对于调节凋亡的C5AR1，我们发现C5AR1的部署会导致小肠降低 组织损伤，辐射后小鼠生存的隐窝细胞凋亡。 C5AR1耗竭会导致非原子和IMUNE类种群中的IL-10表达增加 CX3CR1+巨噬细胞中的信号对于肠损伤防御很重要，C5AR1 - / - 小鼠显着 CX3CR1+巨噬细胞的水平较高。 减弱NF-κB信号传导，而是增加了AKT激活与施加的凋亡减少相关的AKT激活 因此，我们的数据以IL-10的方式表明了针对C5AR1的遗传学或药理学 可以改善结直肠肿瘤模型中的辐射反应反应，同时减少辐射诱导的小肠弓形虫。 这些发现共同表明但抑制措施可能是增加您的一种有前途的方法 放射疗法的治疗窗口。 C5AR1在辐射保护和射线固定1中。 C5AR1 - / - 小鼠的正常上皮（肠，唾液腺和肺上皮）以响应分级为单位 与项目2、3、4和核心B合作的降量放疗。在AIM 2中，我们将调查 抑制C5AR1时的辐射保护的基础。 IL-10台式机制，涉及促进生存和的CX3CR1+巨噬细胞 血管生成3将决定C5AR1如何促进肿瘤细胞与放射疗法的结合。 基于我们的初步数据的假设是C5AR1抑制增加了IL-10分泌，这是 减弱NF-κB信号传导，从而导致IL-10依赖性肿瘤细胞在动物的细胞培养中杀死两者 AIM 4将确定临床级C5AR1的影响 腺体和肺部，并使结直肠肿瘤对放射疗法敏感。 或双月安排，将与我在牛津大学的同事共享数据。 剂量法并将与斯坦福大学的核心B合作，以确保方法的可比性。