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: 10580825
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580825
• 关键词: Acidosis; Adrenal Cortex Hormones; Angiogenesis Inhibitors; Animal Model; Animals; Anti-Inflammatory Agents; Antibodies; Arthritis; Autoimmune; Biological Factors; Blood Vessels; CTLA4 gene; Cancer Patient; Cell Adhesion; 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; Inflammation; Inflammatory; Inflammatory Response; Intestines; Knock-out; Knockout Mice; Knowledge; Leukocytes; Life; Melanoma Cell; Metastatic Melanoma; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Nivolumab; Opportunistic Infections; Pain; Parkinson Disease; Pathologic; Pathway interactions; Patients; 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-PD-1; anti-cancer; antiangiogenesis therapy; antinociception; antitumor effect; cancer immunotherapy; cancer therapy; cancer type; cohort; cytokine; gut inflammation; immune cell infiltrate; immune checkpoint; immune-related adverse events; improved; in vivo; knockout gene; melanoma; member; mortality; mouse model; new therapeutic target; novel; novel strategies; pharmacologic; pre-clinical; programmed cell death ligand 1; programmed cell death protein 1; 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.

项目总结

项目成果

Transwell In Vitro Cell Migration and Invasion Assays.

在体外细胞迁移和侵袭测定法。

• DOI: 10.1007/978-1-0716-3052-5_22
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)

GPR4 Knockout Attenuates Intestinal Inflammation and Forestalls the Development of Colitis-Associated Colorectal Cancer in Murine Models.

• DOI: 10.3390/cancers15204974
• 发表时间: 2023-10-13
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Marie, Mona A.;Sanderlin, Edward J.;Hoffman, Alexander P.;Cashwell, Kylie D.;Satturwar, Swati;Hong, Heng;Sun, Ying;Yang, Li V.
• 通讯作者: Yang, Li V.