Dissecting mechanisms by which PD1 deletions drive aggressive cutaneous T cell lymphoma

剖析 PD1 缺失导致侵袭性皮肤 T 细胞淋巴瘤的机制

• 批准号: 10314443
• 负责人: Jay Daniels
• 金额: $ 4.12万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314443
• 关键词: Dissecting; mechanisms; PD1; deletions; drive

Project Summary/Abstract Cutaneous T-cell lymphoma (CTCL) is a non-Hodgkin lymphoma of skin homing T cells. Although late stage disease has a median survival of less than five years, outcomes are highly heterogenous with some patients surviving <6 months and others >10 years. The molecular mechanisms which drive heterogeneity of disease outcomes in CTCL remain poorly understood. By employing genome sequencing, RNA sequencing, and functional assays in a large cohort of samples, we identified deletion in the gene PDCD1, which encodes the co- inhibitory receptor PD1, as a major driver of differences in CTCL patient phenotypes. We found that PD1- deletions led to increased ex vivo proliferation and cytokine production, decreased expression of exhaustion markers, and reduced signatures of T cell exhaustion, a dysfunctional state of T cells that limits effector functions. Furthermore, in a multi-institution cohort, we found that PD1 deletions predict a significantly worse overall survival. Therefore, in this proposal, we aim to mechanistically dissect the pathways that govern aggressive phenotypes in PD1-deleted CTCL samples. Our preliminary RNAseq data indicates that two key pathways, mTOR-related metabolic pathways and activity of a transcription factor FOXM1, are upregulated in PD1-deleted CTCLs. In Aim 1, we will utilize CTCL cells and primary patient samples to determine whether mTOR drives PD1-dependent metabolism, T cell exhaustion, and growth. We will determine whether PD1 signaling is sufficient to suppress mTOR, the PD1 dependent changes in CTCL metabolism, and whether mTOR signaling is necessary for the growth and un-exhausted phenotype of PD1-deleted CTCLs. In Aim 2, we will utilize CTCL cells and primary patient samples to test first whether FOXM1 is activated downstream of PD1 signaling, then systematically identify FOXM1 target genes in CTCL, and finally test whether FOXM1 is necessary and sufficient for the growth of PD1-deleted CTCLs. Because there are pharmacological inhibitors of both mTOR and FOXM1, our work will address whether PD1 deletions may predict responses to novel classes of CTCL therapeutics, and thus new therapeutic avenues for patients with the most aggressive disease. My overall career goal is to become a successful, independent physician-scientist. The rigorous training plan proposed in this fellowship will allow me to achieve that goal by gaining research skills and knowledge in cellular immunology, cancer signaling pathways, and metabolism. I will be mentored by Dr. Jaehyuk Choi, an expert physician-scientist in CTCL, and Dr. Stephen Miller, a world-renowned T cell biologist, who have devised a joint training plan to develop all necessary research skills, communication skills and promote my professional development. This fellowship will broaden our understanding of CTCL pathogenesis and identify potential novel therapeutic strategies, as well as provide the necessary foundation for my future career as a physician-scientist.

项目摘要/摘要 皮肤T细胞淋巴瘤(CTCL)是一种皮肤归巢T细胞的非霍奇金淋巴瘤。虽然是后期 疾病的中位生存期不到五年，一些患者的结局高度不同 存活6个月，其他人存活10年。驱动疾病异质性的分子机制 CTCL的结果仍然鲜为人知。通过采用基因组测序、RNA测序和 在大量样本的功能分析中，我们发现了PDCD1基因的缺失，该基因编码了 抑制受体PD1，作为CTCL患者表型差异的主要驱动因素。我们发现PD1- 缺失导致体外增殖和细胞因子产生增加，力竭表达减少 标记物，以及T细胞耗竭的特征减少，T细胞的功能失调状态限制了效应器的功能。 此外，在多个机构的队列中，我们发现PD1缺失预示着总体上更糟糕 生死存亡。因此，在这项提议中，我们的目标是机械地剖析支配攻击性的路径 PD1缺失的CTCL样本中的表型。我们的初步RNAseq数据表明，有两条关键途径， PD1缺失的mTOR相关代谢途径和转录因子FOXM1的活性上调 CTCL。在目标1中，我们将利用CTCL细胞和初级患者样本来确定mTOR是否会驱动 依赖PD1的新陈代谢、T细胞耗竭和生长。我们将确定PD1信令是否足够 为了抑制mTOR，依赖PD1的CTCL代谢改变，以及mTOR信号是否 对于PD1缺失的CTCL的生长和未耗尽表型是必需的。在目标2中，我们将使用CTCL 细胞和初级患者样本，首先测试FOXM1是否在PD1信号下游被激活，然后 系统地鉴定CTCL中FOXM1的靶基因，并最终检验FOXM1是否充分必要条件 用于PD1缺失的CTCL的生长。因为mTOR和FOXM1都有药物抑制剂， 我们的工作将解决PD1缺失是否可以预测对新型CTCL疗法的反应，以及 从而为患有最具侵袭性疾病的患者开辟了新的治疗途径。我的整个职业目标是成为 一位成功的、独立的内科医生兼科学家。在此奖学金中提出的严格的培训计划将使 我希望通过获得细胞免疫学、癌症信号转导等方面的研究技能和知识来实现这一目标 途径和新陈代谢。我将得到CTCL内科专家兼科学家蔡在赫博士的指导，以及 世界著名的T细胞生物学家斯蒂芬·米勒博士设计了一项联合训练计划，以发展ALL 必要的研究能力、沟通能力和促进我的专业发展。这一团契将 扩大我们对CTCL发病机制的理解，确定潜在的新治疗策略，以及 为我未来的内科科学家职业生涯奠定了必要的基础。