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

项目摘要/摘要 尽管进行了现代综合治疗，外周T细胞淋巴瘤(PTCL)患者仍在经历 顽固性疾病和早期复发率高。编码细胞程序性死亡的PDCD1基因 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 在最具侵袭性的PTCL亚型中，20%-30%的患者有恶性细胞。的最高频率 在疾病晚期患者中检测到PDCD1缺失，并与较差的 预后。临床试验已发现多例PTCL过度进展或新生发展 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对肿瘤的抑制作用尚不清楚。通过构成这项建议的基础的研究，我们 发现PD-1抑制肿瘤是一种T细胞特异性的生物学机制，可预防恶性T细胞 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 防止致癌脂质的产生，以及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到的概念框架并揭示 PTCL患者癌细胞中的疾病特异性脆弱性可用于治疗。 考虑到PD-1检查点受体在驱动T细胞衰竭和功能障碍中的基础作用 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。 申请人拥有数学/计算生物学的多学科背景，是 医学博士/博士学位毕业的内科医生兼科学家，在PTCL方面有丰富的研究经验。我们提出了一个有重点的 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 完成拟议的研究并开始独立研究事业所需的技能。具体来说，我们 制定了K99期间的五个主要培训目标：i)使用患者来源的PTCL异种移植物 剖析PD-1肿瘤抑制，II)破译代谢通量和致癌脂质的代谢技术 新陈代谢，III)对PD-1信号转导和PTCL癌基因有深入的了解，IV)学习技巧 致癌转录因子网络，以及v)临床翻译。这项培训将在 监督一个由五位世界知名专家组成的杰出指导委员会 域名。培训计划，加上他在计算和分子生物学方面的独特背景，临床 医学和PTCL研究，将把申请者置于非常精选的科学家小组中，他们拥有技能和 有效开展肿瘤抑制PD-1途径的跨学科工作的知识，并将提供 申请人成为PTCL领域成功的独立调查员的基础 病理生物学和临床翻译。

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.