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）的患者将经历疾病进展， 最终死于他们的疾病，因为目前的治疗方法很少治愈， 导致TCL进展和化疗耐药性的原因知之甚少。我们已经证明 抗原呈递细胞，特别是淋巴瘤相关巨噬细胞（LAM）是免疫球蛋白的丰富成分。 TCL中的肿瘤微环境（TME），并直接促进原代TCL细胞的生长和存活 离体。阻断主要组织相容性复合体（MHC），这是抗原呈递和T细胞增殖所必需的。 激活，抑制LAM诱导的恶性T细胞增殖。相反，直接刺激T细胞 原代TCL细胞上的受体（TCR）在转录因子的激活和上调中达到顶峰， 促进常规T细胞的生长和存活，包括锌指转录因子加塔-3。 我们最近发现，加塔-3鉴定了一个分子和临床上不同的TCL亚群， 对化疗很有抵抗力遗传和药理学功能丧失（和功能获得）策略 进一步证明了加塔-3赋予对化疗的抗性。总的来说，我们的初步数据是 这与TCR信号传导和加塔-3依赖性基因表达被利用的假设一致， 恶性T细胞和促进化疗耐药性。缺乏适合遗传学的TCL模型 操作和体内药理学研究阻碍了进一步的进展。因此， 抗原刺激和加塔-3依赖性基因表达促进T细胞淋巴瘤发生， 在天然肿瘤微环境中以及在遗传背景下， 类似人类TCL的景观仍然不确定。我们已经确定了新颖且临床上可以实现的， 针对TCR的治疗策略，我们的目标是扩展这些早期的发现，在这里使用原发性TCL 细胞和患者来源的异种移植物（PDX）。我们的长期目标是了解抗原的作用- 提呈细胞和TME的其他成分在促进T细胞淋巴瘤发生中的作用; 它们提供的淋巴瘤发生因子，包括抗原、共刺激因子和细胞因子受体 依赖;并开发新的治疗策略，利用这些弱点，将改善 这些NHL患者的预后。我们的总体目标是通过以下方式确定机制： 其中TCR和加塔-3在体内促进T细胞淋巴瘤生成。这将通过解决我们的 中心假设TCL进展，包括对化疗的耐药性，是由TCR调节的， 依赖于加塔-3的转录程序。这一假设在我们自己的初步数据中有很好的基础， 这与我们目前对遗传景观和分子发病机制的理解完全一致 TCL的。我们预计，这项研究将为新的研究提供强有力的科学依据。 这些治疗策略最终将在精心设计的临床试验中进行测试。

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.