PSGL-1 mechanisms of T cell exhaustion

联系PD/PI：Tinoco，Roberto 项目摘要 导致抗原持续存在的疾病，如慢性病毒感染和癌症， 耗尽的T细胞（Texs）具有缺陷的效应子功能。虽然特克斯代表了一种改变的状态， 当细胞为了生存而变得依赖于抗原的分化时，它们的功能可以被重新激活。 在抑制性检查点阻断后，导致小鼠、灵长类动物和癌症患者中的抗原控制。而 只有一小部分患者对检查点阻断有反应，许多患者有严重的毒性，特别是 检查点联合治疗。事实上，临床医生预计大多数患者对目前的药物无反应， 免疫疗法强调了识别、开发和改进有效治疗的迫切需要。 并且对于目前没有治疗选择的患者是安全的。我们发现慢性感染PSGL-1 （P-选择素糖蛋白配体-1）缺陷小鼠产生了强有力的抗病毒T细胞应答， 清除，并与多种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。我们的结论是强调我们的发现增强 PSGL-1缺陷小鼠中的抗肿瘤T细胞应答导致PD-1下调和肿瘤控制， 黑素瘤模型。我们的发现将PSGL-1确定为一种新的抑制性检查点， 在慢性病毒感染和癌症期间特克斯的发展。我们提出这项建议的总体目标是 确定PSGL-1信号如何以及何时在慢性抗原刺激期间抑制T细胞。我们的中央 一种假说认为PSGL-1信号不仅调节T细胞中的抑制机制，还调节其他细胞中的抑制机制。 导致T细胞衰竭的免疫细胞。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Texs。拟议的研究将 提供PSGL-1抑制性信号通路何时、何地以及如何介导 特克斯发展。我们将通过以下三个具体目标来检验我们的假设：1）确定 PSGL-1介导的T细胞耗竭的细胞和时间要求2）为了确定治疗性T细胞耗竭， 解除PSGL-1抑制的潜力和3）鉴定PSGL-1介导的分子机制 T细胞中的抑制途径。这一贡献将是重要的，因为了解这种抑制性如何 检查点轴的基本功能有可能导致新的治疗药物的开发 针对一类新的抑制性受体的干预措施，以调节免疫反应， 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的阶级的发展 针对粘附受体抑制途径的药物，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介导的疾病。 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