Evaluate the Role and Mechanism of GPR4 in Immunotherapy-Related Colitis

评估 GPR4 在免疫治疗相关结肠炎中的作用和机制

• 批准号: 10437296
• 负责人: Li Yang
• 金额: $ 7.55万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437296
• 关键词: Acidosis; Adrenal Cortex Hormones; Animal Model; Animals; Anti-Inflammatory Agents; Autoimmune; Biological Factors; Blood Vessels; CTLA4 gene; Cancer Patient; Cell Adhesion; Cell physiology; Cells; Colitis; Combined Modality Therapy; Crohn' s disease; Diarrhea; Endothelial Cells; Endothelium; Exhibits; Family; G-Protein-Coupled Receptors; GPR4 gene; Gatekeeping; Gene Expression; Genes; Genetic; Hepatitis; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intestines; Knock-out; Knockout Mice; Knowledge; Leukocytes; Life; Melanoma Cell; Metastatic Melanoma; Modeling; Morbidity - disease rate; Mouse Protein; Mus; Myocardial Infarction; Nivolumab; Opportunistic Infections; PD-1/PD-L1; Parkinson Disease; Pathologic; Pathway interactions; Patients; Pharmacology; Pneumonia; Predisposing Factor; Progression-Free Survivals; Protons; Pulmonary Inflammation; Refractory; Reporting; Research; Risk; Role; Sampling; Secondary to; Subgroup; Survival Rate; Testing; Thyroiditis; Tissues; Ulcerative Colitis; Vascular Endothelial Cell; Wild Type Mouse; angiogenesis; antagonist; anti-CTLA4; anti-PD-1; anti-PD1 antibodies; anti-cancer; antiangiogenesis therapy; antitumor effect; arthritic pain; base; cancer immunotherapy; cancer therapy; cancer type; cohort; cytokine; gut inflammation; immune activation; immune checkpoint; immune-related adverse events; improved; in vivo; knockout gene; melanoma; member; mortality; mouse model; new therapeutic target; novel; novel strategies; pre-clinical; programmed cell death ligand 1; programmed cell death protein 1; pyridine; response; side effect; standard care; survival outcome; treatment response; tumor; tumor growth; tumorigenic

Project Summary Cancer immunotherapy targeting the immune checkpoints, such as PD-1 (programmed cell death 1)/PD-L1 (programmed death-ligand 1) and CTLA-4 (cytotoxic T lymphocyte associated protein 4), has led to significant anti-tumor effects and overall survival improvement in some cancer patients. Due to hyper- activation of the immune system, however, cancer immunotherapy may also cause mild-to-severe and sometimes life-threatening immune-related adverse events (irAEs). The commons types of inflammatory and autoimmune irAEs include colitis/diarrhea, hepatitis, pneumonitis, thyroiditis, and other inflammatory complications. These irAEs can result in significant morbidity and treatment discontinuation. Biological factors that predispose patients to irAEs after cancer immunotherapy, however, are not well established. Corticosteroids and other immunosuppressive drugs are typically used for the management of irAEs, but some patients are refractory to these treatments. Moreover, systemic immunosuppression associated with immunosuppressive drugs may interfere with the anti-cancer effects of immunotherapy and may also place patients at risk for opportunistic infections such as pneumonia. It is, therefore, important to better understand the mechanisms of irAEs and to develop novel approaches for the management of irAEs. While most irAE research focuses on immune cells and inflammatory cytokines, this project is aimed to interrogate the interface between blood vessels and leukocytes. The proton-sensing G-protein-coupled receptor 4 (GPR4) is highly expressed in vascular endothelial cells and functions as a “gatekeeper” during inflammatory responses via regulating the leukocyte-endothelium interaction. Our recent studies demonstrate that activation of GPR4 stimulates the expression of numerous inflammatory genes in endothelial cells (ECs) and increases leukocyte-EC adhesion. Interestingly, the gene expression of GPR4 is increased by about 5-fold in the inflamed intestinal tissues of ulcerative colitis and Crohn's disease samples when compared to the non-inflamed intestinal tissues. Inhibition of GPR4 has anti-inflammatory, anti- nociceptive, and anti-angiogenic effects. However, the function and mechanism of GPR4 in irAEs and cancer immunotherapy have not been studied. In this project, we will investigate the role and mechanism of GPR4 in cancer immunotherapy and irAEs. GPR4 knockout mice and GPR4 antagonist will be employed to unravel the function of GPR4 in vivo. Mice with melanoma will be treated with anti-CTLA-4/anti-PD-1 immunotherapy in combination with GPR4 inhibition. Using the mouse model, we will (1) determine the role and mechanism of GPR4 in immunotherapy-related colitis and other irAEs; (2) elucidate the effects of GPR4 blockade on anti-cancer immunotherapy.

项目概要 针对免疫检查点的癌症免疫疗法，例如PD-1（程序性细胞死亡1）/PD-L1 （程序性死亡配体 1）和 CTLA-4（细胞毒性 T 淋巴细胞相关蛋白 4），导致 显着的抗肿瘤作用并改善某些癌症患者的总体生存率。由于超 然而，癌症免疫疗法也可能会激活免疫系统，从而导致轻度至重度和 有时会出现危及生命的免疫相关不良事件 (irAE)。常见的炎症类型 自身免疫性 irAE 包括结肠炎/腹泻、肝炎、肺炎、甲状腺炎和其他炎症 并发症。这些 irAE 可能导致显着的发病率和治疗中断。生物 然而，导致患者在癌症免疫治疗后易发生 irAE 的因素尚未明确。 皮质类固醇和其他免疫抑制药物通常用于治疗 irAE，但 有些患者对这些治疗有抵抗力。此外，与全身性免疫抑制有关 免疫抑制药物可能会干扰免疫疗法的抗癌效果，也可能会导致 有肺炎等机会性感染风险的患者。因此，重要的是要更好地 了解 irAE 的机制并开发管理 irAE 的新方法。 虽然大多数 irAE 研究重点关注免疫细胞和炎症细胞因子，但该项目旨在 检查血管和白细胞之间的界面。质子感应 G 蛋白偶联 受体4（GPR4）在血管内皮细胞中高表达，在血管内皮细胞中发挥“看门人”的作用。 通过调节白细胞-内皮相互作用来调节炎症反应。我们最近的研究 证明 GPR4 的激活刺激了许多炎症基因的表达 内皮细胞 (EC) 并增加白细胞与 EC 的粘附。有趣的是，GPR4的基因表达是 溃疡性结肠炎和克罗恩病样本的发炎肠道组织中增加了约 5 倍 与未发炎的肠道组织相比。抑制 GPR4 具有抗炎、抗 伤害感受和抗血管生成作用。然而，GPR4 在 irAE 和 尚未研究癌症免疫疗法。 在这个项目中，我们将研究GPR4在癌症免疫治疗和irAE中的作用和机制。 GPR4 敲除小鼠和 GPR4 拮抗剂将用于揭示 GPR4 的体内功能。小鼠 黑色素瘤患者将接受抗 CTLA-4/抗 PD-1 免疫疗法与 GPR4 联合治疗 抑制。使用小鼠模型，我们将 (1) 确定 GPR4 在 免疫治疗相关结肠炎和其他 irAE； (2)阐明GPR4阻断的抗癌作用 免疫疗法。