The GPR171 pathway in cancer immunotherapy

项目摘要 建议研究项目的科学摘要 免疫检查点阻滞剂疗法彻底改变了我们癌症治疗的临床方法。然而， 总体有效率仍有提高空间，不同癌症类型的有效率差异很大。这个 免疫检查点在T细胞免疫中多余但独特的作用促使我们进一步研究 癌症治疗中的新免疫检查点。BigLEN/GPR171相互作用是一种新发现的GPCR 已报道的调节食物摄取和焦虑的途径。虽然GPR171通常用作 T细胞信号基因，其在T细胞免疫中的潜在作用尚未被探索。我们最近的研究表明 提示GPR171/BigLEN轴是一种新的T细胞检查点通路，可在癌症发生中进行调节 免疫疗法。我们发现GPR171在T细胞中转录，其蛋白表达是在 抗原刺激。神经肽配体BigLEN与GPR171相互作用抑制T细胞受体- 介导信号转导途径，抑制T细胞增殖。T细胞GPR171缺失导致多动 对抗原刺激和GPR171缺陷小鼠表现出增强的抗肿瘤免疫。封锁GPR171 在不同的小鼠肿瘤模型中，拮抗剂的信号传递促进抗肿瘤T细胞免疫。我们的预赛 数据进一步表明，GPR171可能是T细胞上大麻素的抑制性受体。在建议的 在这项研究中，我们将剖析GPR171配体在GPR171介导的抗肿瘤抑制中的作用。我们将进一步 确定GPR171信号抑制抗癌T细胞反应的分子机制。该方法 用于癌症治疗的GPR171阻滞剂将在包括嵌合抗原在内的临床肿瘤模型中进行测试 受体T细胞治疗和人源化小鼠模型联合抗PD-1治疗。通过完成 这些研究，我们发现GPR171是大麻素的受体，这将有助于更好地理解 大麻使用在癌症治疗中的影响，更重要的是，为癌症提供了新的策略 免疫疗法。

Project Summary Scientific Abstract of proposed research project Immune checkpoint blocker therapy has revolutionized our clinical approach in cancer therapy. However, the overall response rate still has room for improvement and varies greatly in different cancer types. The redundant but unique role of immune checkpoints in T cell immunity propels us to further study the role of novel immune checkpoints in cancer therapy. The BigLEN/GPR171 interaction is a newly identified GPCR pathway that has been reported to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene, its potential role in T cell immunity has not been explored. Our recent studies have implicated that the GPR171/BigLEN axis is a new T cell checkpoint pathway that can be modulated for cancer immunotherapy. We found that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor- mediated signaling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171-deficient mice exhibit enhanced antitumor immunity. Blockade of GPR171 signaling by an antagonist promotes antitumor T cell immunity in various mouse tumor models. Our preliminary data further implicate that GPR171 can be an inhibitory receptor on T cell for cannabinoids. In the proposed study, we will dissect the role of GPR171 ligands in GPR171-mediated antitumor suppression. We will further determine the molecular mechanisms that GPR171 signaling inhibits anticancer T cell response. The approach of GPR171 blockade for cancer therapy will be tested in clinical tumor models, including chimeric antigen receptor T-cell therapy and humanized mouse model together with anti- PD-1 therapy. By the completion of these studies, our discovery that GPR171 is a receptor for cannabinoids will help to better understand the impact of cannabis usage in cancer treatment, more importantly, provide new strategies of cancer immunotherapy.