Targeting GPR84 to Overcome Macrophage Mediated Resistance to Immunotherapy

靶向 GPR84 克服巨噬细胞介导的免疫治疗耐药性

基本信息

批准号：
10660122
负责人：
Gang Xin
金额：
$ 36.07万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-18 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660122
关键词：
Ablation Address Affect Agonist Biochemical Bladder Neoplasm CCAAT-Enhancer-Binding Protein-beta Cancer Model Cancer Patient Cells Chromatin Clinical Coupled Cyclic AMP Data Data Set Development Epigenetic Process Exhibits Family Fatty Acids Flow Cytometry Fostering Foundations G-Protein-Coupled Receptors GPR84 gene GTP-Binding Proteins Genetic Genetic Transcription Goals Human Immune response Immunity Immunologic Stimulation Immunotherapy Knowledge Macrophage Malignant Neoplasms Malignant neoplasm of urinary bladder Maps Mediating Metabolic Metabolism Methods Modeling Molecular Monoclonal Antibody Therapy Mus Myelogenous Myeloid Cells NF-kappa B Nonesterified Fatty Acids PD-1 blockade Pathway interactions Patients Phenotype Process Production Publishing Resistance Role Shapes Signal Pathway Signal Transduction Signaling Molecule T cell response T-Lymphocyte TNF gene Therapeutic Tumor Escape Tumor-associated macrophages Work anti-PD-1 arginase design effective therapy efficacy evaluation fatty acid oxidation genome-wide high dimensionality immune checkpoint blockade immune function immunoregulation immunosuppressive macrophages insight loss of function member mouse model novel therapeutic intervention pharmacologic precision medicine prevent programs receptor response sensor signature molecule therapeutic target transcription factor transcriptome tumor tumor growth tumor microenvironment tumor-immune system interactions tumorigenic

项目摘要

Project Summary Immune checkpoint blockade (ICB) has produced extraordinary clinical responses in more than 25 tumor types. However, only a small number of patients benefit from this therapy owing to the immunosuppressive tu- mor microenvironment (TME). As one of the major components of the TME, tumor-associated macrophages (TAMs) usually possess profound inhibitory activity against tumor-killing T cells and facilitate tumor escape from immunotherapy. Clinical findings have shown that the presence of suppressive pro-tumorigenic TAMs correlates with reduced survival in bladder cancer patients treated with immunotherapy. Due to the plasticity of macrophages, excitement has been growing to reshape the pro-tumorigenic TAMs toward the anti-tumorigenic phenotype to stimulate the immunity against cancer. Emerging evidence reveals that this process of macro- phage polarization is inextricably affected by metabolites in the TME, such as free fatty acid (FFA). Lack of data regarding the role of FFA signals in macrophages prevents us from designing an elegant approach to re- polarizing TAM to foster a better anti-tumor T cell response. We propose to dissect the molecular basis of the FFA-mediated signal pathway in TAMs differentiation and its role in resistance to PD-1 blockade, which can be leveraged to restore sensitivity to ICB therapy. Our analysis of published datasets revealed that TAMs from human bladder tumors uniquely express elevated levels of a fatty acid receptor, G Protein-Coupled Receptor 84 (GPR84). These GPR84 expressing cells exhibited enriched hallmarks of anti-tumorigenic function com- pared to their counterpart. Further analysis reveals that expression of GPR84 significantly correlates with longer survival in bladder cancer patients. Our work shows that genetic ablation of GPR84 leads to enhanced production of inhibitory molecules including Arginase 1 via activation of CCAAT/enhancer-binding protein beta (C/EBPβ). By contrast, GPR84 activation by its agonist 6-OAU can reprogram pro-tumorigenic macrophages to produce anti-tumorigenic signature molecules, such as tumor necrosis factor-α (TNFα). Mechanistically, we found that GPR84 potentiates the activity of Nuclear factor kappa B (NF-κB) to enhance TNFα production. Central hypothesis: GPR84 serves as a metabolic signaling checkpoint for determining the function of macro- phage by restricting the immunosuppressive while promoting the immune-stimulating phenotype. Treatment with GPR84 agonists significantly retards tumor growth and increases the anti-tumor efficacy of anti-PD-1 mAb therapy in a MB49 bladder cancer model. Aim 1: Determine whether the lack of GPR84 promotes the polariza- tion of immunosuppressive TAMs. Aim 2: Dissect the molecular and epigenetic mechanisms by which GPR84 signaling promotes an immune-stimulating phenotype in macrophages. Aim 3: Determine whether targeting GPR84-mediated macrophage repolarization enhances the anti-tumor efficacy of ICB. Results will inform the development of promising treatments to reshape immunosuppressive TME through manipulation of metabolic signaling, and thereby restore responsiveness to PD-1 blockade for bladder cancer patients.

项目概要免疫检查点阻断 (ICB) 在超过 25 种肿瘤中产生了非凡的临床反应然而，由于免疫抑制作用，只有少数患者从这种疗法中受益。 mor微环境（TME）作为TME的主要组成部分之一，肿瘤相关巨噬细胞。 (TAM) 通常对肿瘤杀伤 T 细胞具有深刻的抑制活性并促进肿瘤逃逸临床研究结果表明，抑制性促肿瘤 TAM 的存在。由于免疫治疗的可塑性，与膀胱癌患者的生存率降低相关。巨噬细胞，人们越来越兴奋地将促肿瘤 TAM 重塑为抗肿瘤肿瘤新出现的证据表明，这一宏观过程噬菌体极化不可避免地受到 TME 中代谢物的影响，例如游离脂肪酸 (FFA) 的缺乏。有关 FFA 信号在巨噬细胞中作用的数据使我们无法设计一种优雅的方法来重新我们建议剖析 TAM 的分子基础，以促进更好的抗肿瘤 T 细胞反应。 FFA 介导的 TAM 分化信号通路及其在抵抗 PD-1 阻断中的作用，可我们对已发表的数据集的分析表明，TAM 来自于恢复对 ICB 治疗的敏感性。人类膀胱肿瘤独特地表达升高水平的脂肪酸受体、G蛋白偶联受体 84 (GPR84)。这些 GPR84 表达细胞表现出丰富的抗肿瘤功能特征。进一步的分析表明，GPR84 的表达与它们显着相关。我们的工作表明，GPR84 的基因消除可提高膀胱癌患者的生存期。通过激活 CCAAT/增强子结合蛋白 beta 产生包括精氨酸酶 1 在内的抑制分子 (C/EBPβ) 相比之下，GPR84 的激动剂 6-OAU 激活可以将促肿瘤巨噬细胞重新编程为从机制上讲，我们产生抗肿瘤标志分子，例如肿瘤坏死因子-α（TNFα）。发现 GPR84 增强核因子 kappa B (NF-κB) 的活性，从而增强 TNFα 的产生。中心假设：GPR84 作为代谢信号检查点，用于确定宏观调控的功能通过限制免疫抑制同时促进免疫刺激表型来治疗噬菌体。与 GPR84 激动剂联合使用可显着延缓肿瘤生长并提高抗 PD-1 mAb 的抗肿瘤功效 MB49 膀胱癌模型中的治疗目标 1：确定 GPR84 的缺乏是否会促进极化。目标 2：剖析 GPR84 的分子和表观遗传机制。目标 3：确定是否定位 GPR84 介导的巨噬细胞复极化增强了 ICB 的抗肿瘤功效。开发有前景的治疗方法，通过代谢调控重塑免疫抑制性 TME 信号传导，从而恢复膀胱癌患者对 PD-1 阻断的反应性。