PD-1 tumor suppressor mechanims in peripheral T-cell lymphoma

PD-1在外周T细胞淋巴瘤中的抑癌机制

• 批准号: 10581151
• 负责人: Tim Wartewig
• 金额: $ 11.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581151
• 关键词: ATAC-seq; ATP Citrate (pro-S)-Lyase; Anabolism; Automobile Driving; Biological; Biological Assay; Biological Models; Biotin; CRISPR screen; Cellular biology; Cholesterol; Clinical; Clinical Medicine; Clinical Trials; Combined Modality Therapy; Computational Biology; DNA; Data; Development; Development Plans; Disease; Doctor of Medicine; Doctor of Philosophy; Energy Metabolism; Enzymes; Epigenetic Process; Family member; Foundations; Frequencies; Functional disorder; Gatekeeping; Genes; Genetic; Genetic Engineering; Glucose; Glutathione; Goals; Homeostasis; Human; Immune checkpoint inhibitor; Immunologic Receptors; Individual; Inferior; JUN gene; Knowledge; Lipids; Lymphoma; Lymphoma cell; Lymphomagenesis; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Mathematics; Mediating; Mentors; Metabolic; Metabolism; Modernization; Molecular; Molecular Biology; Mus; Mutate; Mutation; Nature; Neoplasms; Oncogenes; Oncogenic; Pathway interactions; Patients; Peripheral; Physicians; Production; Prognosis; Refractory Disease; Regulation; Relapse; Research; Research Personnel; Risk Factors; Role; Scientist; Signal Transduction; Supervision; Survival Rate; T-Cell Lymphoma; T-Cell Transformation; T-Lymphocyte; Techniques; Testing; Therapeutic; Training; Transcription Factor AP-1; Tumor Immunity; Tumor Suppression; Tumor Suppressor Proteins; Work; Xenograft Model; Xenograft procedure; advanced disease; anti-PD-1; cancer cell; career; career development; checkpoint receptors; clinical translation; cytotoxicity; design; exhaustion; experience; glucose metabolism; human data; immune checkpoint; innovation; insight; lipid biosynthesis; lipid metabolism; lipidome; lipidomics; member; mouse model; multidisciplinary; new therapeutic target; novel; nucleotide metabolism; patient derived xenograft model; pharmacologic; prevent; programmed cell death protein 1; programs; restraint; skills; stable isotope; survival outcome; transcription factor; transcriptome sequencing; transcriptomics; tumor; tumor microenvironment; tumorigenic

PROJECT SUMMARY/ABSTRACT Despite modern combination therapies, patients with peripheral T-cell lymphoma (PTCL) continue to experience high rates of refractory disease and early relapse. The PDCD1 gene, which encodes the programmed cell death protein 1 (PD-1) immune checkpoint receptor, is a key tumor suppressor in T-cells and is inactivated in the malignant cells of 20%–30% of patients across most aggressive PTCL subtypes. The highest frequencies of PDCD1 deletions have been detected in patients with advanced disease stages and are associated with a poor prognosis. Clinical trials have revealed multiple cases of PTCL hyperprogression or de novo development after anti-PD-1 checkpoint inhibitor treatment. Despite this, the molecular and tumor biological mechanism underlying the PD-1 tumor suppression remain unclear. Through the studies that form the basis of this proposal, we discovered that PD-1 tumor suppression is a T-cell-specific biological mechanism to prevent malignant T-cell transformation at three distinct levels: i) PD-1 inhibits oncogene-triggered metabolic reprogramming, ii) PD-1 safeguards against tumorigenic lipid production, and iii) PD-1 suppresses oncogenic transcription factor programs. The proposed studies will establish this previously unrecognized conceptual framework and uncover disease-specific vulnerabilities in cancer cells of patients with PTCLs that can be exploited for therapy. Considering the fundamental role of the PD-1 checkpoint receptor in driving T-cell exhaustion and dysfunction in tumor microenvironments, we predict that our results will have broader implications for T-cell biology. The applicant has a multidisciplinary background in mathematics/computational biology and is an M.D./Ph.D.-trained physician-scientist with extensive research experience in PTCLs. We propose a focused career development plan during which the applicant will be trained in the technical, conceptual, and professional skills required to complete the proposed studies and launch an independent research career. Specifically, we have developed five major training goals for the K99 period: i) utilization of patient-derived PTCL xenografts to dissect PD-1 tumor suppression, ii) metabolic techniques to decipher metabolic flux rates and oncogenic lipid metabolism, iii) a thorough understanding of PD-1 signal transduction and PTCL oncogenes, iv) skills to study oncogenic transcription factor networks, and v) clinical translation. This training will be carried out under the supervision of an outstanding mentoring committee consisting of five world-renowned experts in exactly these domains. The training plan, together with his unique background in computational and molecular biology, clinical medicine, and PTCL research, will place the applicant among a very select group of scientists with the skills and knowledge to effectively pursue interdisciplinary work on the tumor suppressive PD-1 pathway, and will provide the foundation for the applicant to become a successful independent investigator in the field of PTCL pathobiology and clinical translation.

项目总结/摘要 尽管有现代联合治疗，外周T细胞淋巴瘤（PTCL）患者仍持续经历 难治性疾病和早期复发率高。PDCD 1基因编码程序性细胞死亡 蛋白1（PD-1）免疫检查点受体，是T细胞中的关键肿瘤抑制因子，在T细胞中失活。 在大多数侵袭性PTCL亚型中，20%-30%的患者存在恶性细胞。最高频率的 PDCD 1缺失已在晚期疾病患者中检测到，并且与不良的免疫反应相关。 预后临床试验已经揭示了多例PTCL超进展或新发病例， 抗PD-1检查点抑制剂治疗。尽管如此，潜在的分子和肿瘤生物学机制 PD-1肿瘤抑制仍不清楚。通过构成本建议基础的研究，我们 发现PD-1肿瘤抑制是一种T细胞特异性生物学机制，可以防止恶性T细胞肿瘤的发生。 在三个不同水平的转化：i）PD-1抑制癌基因触发的代谢重编程，ii）PD-1 iii）PD-1抑制致癌转录因子 程序.拟议的研究将建立这一以前未被认识的概念框架，并揭示 PTCL患者的癌细胞中的疾病特异性脆弱性，可以用于治疗。 考虑PD-1检查点受体在驱动T细胞衰竭和功能障碍中的基本作用 在肿瘤微环境中，我们预测我们的结果将对T细胞生物学产生更广泛的影响。 申请人具有数学/计算生物学的多学科背景， 医学博士/博士学位-在PTCL方面具有丰富研究经验的训练有素的医生科学家。我们提出了一个重点 职业发展计划，在此期间，申请人将接受技术，概念和专业培训 完成拟议的研究和开展独立研究所需的技能。我们特别 已经为K99阶段制定了五个主要培训目标：i）利用患者来源的PTCL异种移植物， 剖析PD-1肿瘤抑制，ii）代谢技术，以解读代谢通量率和致癌脂质 代谢，iii）对PD-1信号转导和PTCL癌基因的透彻理解，iv）学习的技能 致癌转录因子网络，和v）临床翻译。这项培训将在 监督一个杰出的指导委员会，由五位世界知名的专家组成， 域.培训计划，加上他在计算和分子生物学，临床 医学和PTCL研究，将把申请人置于一个非常精选的科学家群体中， 知识，以有效地追求跨学科的工作对肿瘤抑制PD-1途径，并将提供 申请人成为PTCL领域成功的独立研究者的基础 病理生物学和临床翻译。