THE T-CELL RECEPTOR'S ROLE IN T-CELL LYMPHOMA PATHOGENESIS

项目摘要 大多数患有T细胞淋巴瘤(TCL)的患者将经历疾病的进展和 最终死于他们的疾病，因为目前的治疗方法很少治愈，以及潜在的机制 推动TCL进展和化疗耐药的机制还知之甚少。我们已经证明了 抗原提呈细胞，特别是淋巴瘤相关巨噬细胞(LAM)是 肿瘤微环境(TME)在TCL中的表达，直接促进原代TCL细胞的生长和存活 体外实验。阻断抗原提呈和T细胞所需的主要组织相容性复合体(MHC) 激活，抑制LAM诱导的恶性T细胞的增殖。相反，T细胞的直接刺激 原代TCL细胞上的受体(TCR)最终激活和上调转录因子，这些转录因子 促进常规T细胞的生长和存活，包括锌指转录因子GATA-3。 我们最近已经证明，GATA-3识别TCL的一个分子和临床上不同的子集，这些子集是 对化疗有高度抵抗力。遗传和药理学功能丧失(和功能获得)策略 进一步证明GATA-3对化疗具有耐药性。总的来说，我们的初步数据是 与TCR信号和依赖于GATA-3的基因表达被 恶性T细胞并促进化疗耐药。缺乏适用于遗传因素的TCL模型 操纵和体内药理研究阻碍了进一步的进展。因此，在多大程度上 抗原刺激和GATA-3依赖的基因表达促进T细胞淋巴肿大和 在天然肿瘤微环境和遗传背景下的化疗耐药性 与人类TCL相似的景观仍不确定。我们已经确定了新颖的，临床上可以实现的， 针对TCR的治疗策略，我们的目标是使用初级TCL扩展这些早期发现 细胞和患者来源的异种移植(PDX)。我们的长期目标是了解抗原的作用- 呈递细胞和TME的其他成分，促进T细胞淋巴瘤的发生；鉴定 它们提供的促淋巴因子，包括抗原、共刺激和细胞因子受体 依赖；并开发新的治疗策略，利用这些脆弱性，将改善 患有这些非霍奇金淋巴瘤患者的预后。我们这里的总体目标是通过以下方式确定机制 其中TCR和GATA-3在体内促进T细胞淋巴瘤的发生。这将通过解决我们的 中心假设TCL的进展，包括对化疗的抵抗，是由TCR-和 依赖GATA-3的转录程序。这一假设基于我们自己的初步数据， 这与我们目前对遗传图景和分子发病机制的理解完全一致 TCL的。我们预计，提出的研究将为小说提供强有力的科学依据 最终将在精心设计的临床试验中进行测试的治疗策略。

Project Abstract The majority of patients afflicted with a T-cell lymphoma (TCL) will experience disease progression and ultimately succumb to their disease, as current therapies are rarely curative, and the underlying mechanisms driving TCL progression and chemotherapy resistance are poorly understood. We have demonstrated that antigen-presenting cells, particularly lymphoma-associated macrophages (LAM) are abundant constituents of the tumor microenvironment (TME) in TCL, and directly promote the growth and survival of primary TCL cells ex vivo. Blockade of the major histocompatibility complex (MHC), required for antigen presentation and T-cell activation, inhibits LAM-induced proliferation of malignant T cells. Conversely, direct stimulation of the T-cell receptor (TCR) on primary TCL cells culminates in the activation and upregulation of transcription factors that promote the growth and survival of conventional T cells, including the zinc-finger transcription factor GATA-3. We have recently shown that GATA-3 identifies a molecularly and clinically distinct subset of TCL that are highly resistant to chemotherapy. Genetic and pharmacologic loss-of-function (and gain-of-function) strategies further demonstrated that GATA-3 confers resistance to chemotherapy. Collectively, our preliminary data are consistent with the hypothesis that TCR signaling and GATA-3-dependent gene expression are exploited by malignant T cells and promote chemotherapy resistance. A paucity of TCL models amenable to genetic manipulation and pharmacologic in vivo studies has hampered further progress. Therefore, the extent to which antigenic stimulation and GATA-3-dependent gene expression promote T-cell lymphomagenesis and chemotherapy resistance within the native tumor microenvironment, and within the context of a genetic landscape resembling human TCL, remains uncertain. We have identified novel, and clinically achievable, therapeutic strategies targeting the TCR, and we aim to extend those earlier findings here using primary TCL cells and patient-derived xenografts (PDX). Our long-term goals are to understand the role of antigen- presenting cells, and other constituents of the TME, in promoting T-cell lymphomagenesis; to identify the lymphomagenic factors they provide, including those that are antigen, costimulatory, and cytokine receptor dependent; and to develop novel therapeutic strategies exploiting these vulnerabilities that will improve outcomes for patients afflicted with these NHL. Our overall objective here is to determine the mechanisms by which the TCR and GATA-3 promote T-cell lymphomagenesis in vivo. This will be achieved by addressing our central hypothesis that TCL progression, including resistance to chemotherapy, is regulated by TCR- and GATA-3-dependent transcriptional programs. This hypothesis is well grounded in our own preliminary data, and is entirely consistent with our current understanding of the genetic landscape and molecular pathogenesis of the TCL. We anticipate that the research proposed will provide a strong scientific rationale for novel therapeutic strategies that will ultimately be tested in well-designed clinical trials.