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.

项目概要/摘要 尽管采用现代联合疗法，外周 T 细胞淋巴瘤 (PTCL) 患者仍继续经历 难治性疾病和早期复发率很高，PDCD1 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 在最具侵袭性的 PTCL 亚型中，20%–30% 的患者存在恶性细胞。 PDCD1 缺失已在疾病晚期患者中检测到，并且与较差的健康状况相关。 临床试验显示多例 PTCL 过度进展或术后重新发展。 尽管如此，抗 PD-1 检查点抑制剂治疗的分子和肿瘤生物学机制仍然存在。 PD-1 肿瘤抑制作用仍不清楚。通过构成该提议基础的研究，我们发现。 发现PD-1肿瘤抑制是T细胞特异性的生物学机制，防止T细胞恶性化 在三个不同水平上的转化：i) PD-1 抑制癌基因触发的代谢重编程，ii) PD-1 防止致瘤脂质产生，以及 iii) PD-1 抑制致癌转录因子 拟议的研究将建立这个以前未被认识的概念框架并揭示。 PTCL 患者癌细胞中疾病特异性的脆弱性可用于治疗。 考虑 PD-1 检查点受体在驱动 T 细胞耗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，并且是 受过 M.D./Ph.D. 培训的医师科学家，在 PTCL 领域拥有丰富的研究经验。 职业发展计划，在此期间申请人将接受技术、概念和专业方面的培训 具体来说，我们需要完成拟议的研究并开展独立研究生涯所需的技能。 制定了 K99 时期的五个主要培训目标：i) 利用患者来源的 PTCL 异种移植物 剖析 PD-1 肿瘤抑制，ii) 代谢技术破译代谢通量率和致癌脂质 新陈代谢，iii) 对 PD-1 信号转导和 PTCL 癌基因的透彻理解，iv) 学习技能 致癌转录因子网络，以及 v) 临床转化。 由五位世界知名专家组成的优秀导师委员会进行监督 培训计划以及他在计算和分子生物学、临床方面的独特背景。 医学和 PTCL 研究，将使申请人跻身于经过精心挑选的具有技能和能力的科学家群体之中。 有效开展肿瘤抑制性 PD-1 通路跨学科工作的知识，并将提供 为申请人成为PTCL领域成功的独立研究者奠定基础 病理生物学和临床翻译。