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:
  • 金额:
    $ 36.07万
  • 依托单位:
  • 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

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.
项目摘要 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。 类型然而,只有少数患者受益于这种治疗,由于免疫抑制的肿瘤, 莫尔微环境(TME)。肿瘤相关巨噬细胞作为TME的主要成分之一, TAMs通常对肿瘤杀伤性T细胞具有显著的抑制活性,并促进肿瘤逃逸。 免疫疗法。临床研究结果表明,抑制性促肿瘤TAM的存在, 与接受免疫治疗的膀胱癌患者的生存率降低相关。由于塑料的可塑性, 巨噬细胞,兴奋已经越来越多地重塑促肿瘤发生的TAM向抗肿瘤发生的TAM。 表型以刺激针对癌症的免疫力。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中代谢物如游离脂肪酸(FFA)的影响。缺乏 关于FFA信号在巨噬细胞中的作用的数据阻止了我们设计一种优雅的方法来重新定位, 极化TAM以促进更好的抗肿瘤T细胞应答。我们建议剖析的分子基础, FFA介导的TAMs分化中的信号通路及其在PD-1阻断抗性中的作用, 用于恢复对ICB治疗的敏感性。我们对已发表数据集的分析显示,来自 人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)。这些表达GPR 84的细胞表现出抗肿瘤发生功能的富集标志, 对他们的对手。进一步的分析表明,GPR 84的表达显著相关, 膀胱癌患者的生存期更长。我们的工作表明,GPR 84的基因切除导致增强的 通过激活CCAAT/增强子结合蛋白β产生包括精氨酸酶1的抑制性分子 (C/EBPβ)。相比之下,GPR 84被其激动剂6-OAU激活可以重编程促肿瘤发生巨噬细胞, 产生抗肿瘤信号分子,如肿瘤坏死因子-α(TNFα)。机械地,我们 发现GPR 84增强核因子κ B(NF-κB)的活性以增强TNFα的产生。 中心假设:GPR 84作为一个代谢信号检查点,用于确定巨噬细胞的功能。 噬菌体通过限制免疫抑制同时促进免疫刺激表型。治疗 显著延缓肿瘤生长并增加抗PD-1 mAb的抗肿瘤功效 在MB 49膀胱癌模型中的治疗。目的1:确定GPR 84的缺乏是否促进了极化, 免疫抑制性TAM的作用。目的2:剖析GPR 84基因表达的分子和表观遗传机制, 信号传导促进巨噬细胞中的免疫刺激表型。目标3:确定目标是否 GPR 84介导的巨噬细胞复极化增强ICB的抗肿瘤功效。结果将通知 开发有前途的治疗方法,通过操纵代谢,重塑免疫抑制性TME, 因此,在膀胱癌患者中,PD-I阻断剂的作用是通过抑制PD-I信号传导,从而恢复对PD-I阻断的响应性。

项目成果

期刊论文数量(1)
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