PSGL-1 mechanisms of T cell exhaustion

联系PD/PI：提诺科，罗伯托 项目总结 导致抗原持久性的疾病，如慢性病毒感染和癌症，会导致 效应器功能有缺陷的耗尽T细胞(TES)。而TES代表了一种改变的状态 细胞为生存而对抗原上瘾的分化过程，其功能可以恢复。 在抑制检查点阻断后，在小鼠、灵长类动物和癌症患者中导致抗原控制。而当 只有一小部分患者对检查站封锁有反应，许多人有严重的毒性，特别是 检查点综合疗法。事实上，临床医生预计大多数患者对当前的 免疫疗法突出了识别、开发和改进有效治疗方法的迫切需要。 对于目前没有治疗选择的患者来说是安全的。我们发现慢性感染PSGL-1 (P-选择素糖蛋白配体-1)缺陷小鼠表现出强大的抗病毒T细胞反应，支持病毒 清除和与多个抑制性受体的下调有关表明PSGL-1 代表了免疫调节的新靶点。我们的结论被我们发现增强的 PSGL-1缺陷小鼠的抗肿瘤T细胞反应导致PD-1表达下调和肿瘤控制 黑色素瘤模型。我们的发现确定PSGL-1是一个新的抑制检查点，它促进 TES在慢性病毒感染和癌症过程中的发展。我们这项建议的总体目标是 确定PSGL-1信号在慢性抗原刺激过程中如何以及何时抑制T细胞。我们的中央 假设PSGL-1信号不仅在T细胞中调节抑制机制，而且在其他 导致T细胞耗尽的免疫细胞。其基本原理是，一旦我们完全理解了这条途径， 我们可以开发针对PSGL-1的有效疗法来重振TES。拟议的研究将 对PSGL-1抑制信号通路何时、何地以及如何进行机制分析 TES的发展。我们将通过追求以下三个具体目标来验证我们的假设1)以确定 PSGL-1介导的T细胞衰竭的细胞和时间需求2)以确定治疗 解除PSGL-1抑制的可能性和3)确定PSGL-1介导的分子机制 T细胞中的抑制通路。这一贡献将是重大的，因为理解这种抑制是如何 检查点轴线的基本功能有可能导致新疗法的开发 针对一类新的抑制性受体的干预措施，以调节免疫反应并帮助预防和 治疗多种疾病。我们的研究是创新的，因为它们可能会扩大一个新阶层的发展 针对黏附受体抑制通路的药物，以逆转T细胞耗竭。了解 PSGL-1介导抑制信号的机制有望帮助开发新的治疗方法 由免疫细胞功能障碍引起的疾病。 项目摘要/摘要第6页

Contact PD/PI: Tinoco, Roberto PROJECT SUMMARY Diseases leading to antigen persistence as in chronic viral infection and cancer induce development of exhausted T cells (Texs) that have defective effector function. While Texs represent an altered state of differentiation in which cells become addicted to antigen for their survival, their functions can be reinvigorated after inhibitory checkpoint blockade, leading to antigen control in murine, primate, and cancer patients. While only a small subset of patients responds to checkpoint blockade, many have severe toxicities especially with checkpoint combination therapy. The fact that clinicians expect most patients to be non-responsive to current immunotherapies highlights the pressing need to identify, develop, and improve treatments that are efficient and safe for patients that presently have no treatment options. Our discovery that chronically infected PSGL-1 (P-selectin glycoprotein ligand-1)-deficient mice mounted a robust anti-viral T cell response that supported viral clearance and was linked to downregulation of multiple inhibitory receptors demonstrates that PSGL-1 represents a new target for immune modulation. Our conclusion is underscored by our finding of enhanced anti-tumor T cell responses in PSGL-1-deficient mice leading to PD-1 downregulation and tumor control in a melanoma model. Our findings identified PSGL-1 as a new inhibitory checkpoint that promotes the development of Texs during chronic viral infection and cancer. Our overall objective in this proposal is to determine how and when PSGL-1 signaling inhibits T cells during chronic antigen stimulation. Our central hypothesis is that PSGL-1 signaling modulates inhibitory mechanisms not only in T cells but also in other immune cells that contribute to T cell exhaustion. The rationale is that once we fully understand this pathway, we can develop effective therapeutics targeting PSGL-1 to reinvigorate Texs. The proposed research will provide a mechanistic analysis of when, where, and how the PSGL-1 inhibitory signaling pathway mediates Texs development. We will test our hypothesis by pursuing the following three specific aims 1) To determine the cellular and temporal requirement for PSGL-1 mediated T cell exhaustion 2) To determine the therapeutic potential of relieving PSGL-1 inhibition and 3) To identify molecular mechanisms by which PSGL-1 mediates inhibitory pathways in T cells. This contribution will be significant because understanding how this inhibitory checkpoint axis fundamentally functions has the potential to lead to the development of new therapeutic interventions targeting a new class of inhibitory receptors to modulate immune responses and help prevent and treat a wide range of diseases. Our studies are innovative as they may expand the development of a new class of drugs targeting adhesion receptor inhibitory pathways to reverse T cell exhaustion. Understanding the mechanisms by which PSGL-1 mediates inhibitory signals is anticipated to help develop new therapies for diseases mediated by immune cell dysfunction. Project Summary/Abstract Page 6