Molecular mechanisms underlying T cell resistance to PD-1 signaling

T 细胞抵抗 PD-1 信号传导的分子机制

• 批准号: 10714460
• 负责人: Anna S Tocheva
• 金额: $ 42.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714460
• 关键词: Advanced Development; Affinity; Autoimmunity; Automobile Driving; Bar Codes; Binding; Biology; Blocking Antibodies; Cancer Patient; Cellular biology; Clinical; Complex; Data; Dependence; Development; Etiology; Foundations; Generations; Genetic Transcription; Heterogeneity; Homeostasis; Human; Immune Tolerance; Immune response; Immunoassay; Immunotherapeutic agent; Infection; Inflammatory; Knowledge; Ligands; Maintenance; Malignant Neoplasms; Mediating; Mediator; Memory; Molecular; Molecular Profiling; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Population; Research; Resistance; Role; Shapes; Signal Transduction; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; T-cell diversity; T-cell inflamed; Tissues; Toxic effect; Tumor Escape; autoreactivity; effector T cell; functional genomics; improved; novel therapeutics; phosphoproteomics; prevent; programmed cell death ligand 1; programmed cell death protein 1; programs; receptor; single-cell RNA sequencing; targeted treatment; tumor

ABSTRACT T cell activation initiates a program of differentiation that generates a continuum of different memory T cell states with diverse functional and molecular profiles. Activated T cells upregulate the inhibitory receptor programmed cell death protein 1 (PD-1) to prevent excessive T cell inflammation, autoreactivity and tissue damage. Upon binding to its ligands, PD-1 interferes with the phosphorylation cascade that modulates the quality and quantity of T cell signaling. Cancers evade T cell recognition by engaging PD-1 and consequently PD-1 blocking antibodies restore anti-tumor T cell responses and improve the survival of patients with various malignancies. Unfortunately, the majority of cancer patients do not respond to PD-1 blockade and up to 30% develop inflammatory toxicities highlighting the critical role of PD-1 in the maintenance of immune tolerance. Research into basic PD-1 biology, together with the clinical picture of cancer patients treated with PD-1 blocking antibodies, converge to emphasize that PD-1 engages complex signaling networks to support T cell homeostasis, differentiation and immune responses. Therefore, elucidating the signaling cascades and molecular pathways triggered by PD-1 are paramount to fundamental T cells biology and will lay the foundation for advancing the development of PD-1 targeting therapies. Nevertheless, our knowledge as it pertains to the molecular programs that support PD-1 inhibition in functionally diverse human T cell populations is limited. Furthermore, PD-1 has two ligands with distinct tissues expression patterns and binding affinity, yet the functional consequences of these differences are unknown. Our preliminary data highlight that PD-1 engages unique signaling cascades in ligand specific-manner across the trajectory of naïve to memory differentiation, and that the molecular programs underlying functional, phenotypic and developmental T cell heterogeneity also guide pathways of resistance to PD-1 inhibition. Here we will leverage: (1) quantitative phosphoproteomics to reveal PD-1 ligand specific phosphorylation cascades triggered in functionally distinct T cell populations; (2) functional immuno-assays in combination with scRNA-seq and cellular barcoding to identify transcriptional regulators of PD-1 responsivity across the trajectory of naïve through memory and effector T cell generation; and (3) functional genomics to identify cellular and molecular mediators of resistance to PD-1 inhibition. Successful completion of this proposal will reveal how functional T cell diversity shapes and guides PD-1 triggered cellular and molecular pathways and their associated PD-1 ligand specific dependencies. Collectively, understanding the cellular and molecular etiologies associated with PD-1 responsivity and the mechanisms driving T cell resistance to PD-1 inhibition will further our understanding of the fundamental functions of this critical inhibitory receptor in immunological tolerance and advance novel therapeutic directions targeting PD-1 with implications in cancer, infection and autoimmunity.

抽象的 T细胞激活启动了一个分化程序，该程序生成不同记忆T细胞状态的连续性语言 具有潜水功能和分子谱。激活的T细胞上调了抑制性受体编程 细胞死亡蛋白1（PD-1），以防止T细胞注射过多，自动反应性和组织损伤。之上 PD-1与其配体结合，干扰了调节质量和数量的磷酸化级联反应 T细胞信号传导。癌症通过参与PD-1并因此避免T细胞识别 抗体恢复抗肿瘤T细胞反应并改善各种恶性肿瘤患者的存活率。 不幸的是，大多数癌症患者对PD-1的封锁不反应，最多30％ 炎症毒性突出了PD-1在维持免疫耐受性中的关键作用。研究 进入基本的PD-1生物学，再加上用PD-1阻断抗体治疗的癌症患者的临床图片， 收敛以强调PD-1与复杂的信号网络相关以支持T细胞稳态， 分化和免疫反应。因此，阐明信号级联和分子途径 由PD-1触发对于基本T细胞生物学至关重要，将为推进 PD-1靶向疗法的开发。然而，我们的知识与分子程序有关 该支持在功能多样的人类T细胞群体中的PD-1抑制是有限的。此外，PD-1具有 具有不同组织表达模式和结合亲和力的两个配体，但功能后果 这些差异是未知的。我们的初步数据凸显了PD-1在 在幼稚到记忆分化的整个轨迹的配体特定曼纳和分子程序 潜在的功能，表型和发育性T细胞异质性也指导抗性的途径 PD-1抑制。在这里，我们将利用：（1）定量磷蛋白组学揭示PD-1配体特异性 在功能上不同的T细胞群体中触发的磷酸化级联反应； （2）功能性免疫测定 结合SCRNA-SEQ和细胞条形码，以识别PD-1响应的转录调节剂 通过记忆和效应t细胞产生，整个幼稚的轨迹； （3）功能基因组学 确定对PD-1抑制的耐药性的细胞和分子介质。成功完成此建议 将揭示功能性T细胞多样性形状和指南PD-1如何触发细胞和分子途径以及 它们相关的PD-1配体特定依赖性。总体了解细胞和分子 与PD-1响应性相关的病因以及驱动T细胞抑制T细胞抑制的机制将 进一步，我们对这种关键抑制受体在免疫学中的基本功能的理解 靶向PD-1的耐受性和提高新的治疗方向，对癌症，感染和 自身免疫性。