Towards targeting the lymphoma microenvironment

针对淋巴瘤微环境

• 批准号: 10248398
• 负责人: Hans-Guido Wendel
• 金额: $ 106.2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10248398
• 关键词: Affect; Antibodies; B-Cell Lymphomas; B-Lymphocytes; BCL2 gene; Biological Process; Biology; CREBBP gene; Cell Communication; Cell Cycle Regulation; Cells; Cellular Metabolic Process; Data; Dependence; Development; Disease; EZH2 gene; Elements; Engineering; Epigenetic Process; Follicular Lymphoma; Genetic; Genetic Translation; Genotype; Goals; Human; Immunologic Receptors; Indolent; Intervention; Legal patent; Lymphoma; Lymphoma cell; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Molecular Biology; Mus; Mutation; Pathogenesis; Publications; Reporting; Role; Series; Shapes; Work; base; checkpoint inhibition; chimeric antigen receptor T cells; chronic leukemia; driver mutation; inhibitor/antagonist; leukemia/lymphoma; mouse model; novel therapeutics; public health relevance; single-cell RNA sequencing; success; therapy resistant; tool; tumor

Towards Targeting the Follicular Lymphoma Microenvironment Follicular lymphoma (FL) is the second most common and still incurable form of B cell lymphoma. FL is a slow growing cancer that shows a unique dependence on a supportive microenvironment. The supportive niche also affects FL therapies. For example, inhibitors of BTK, PI3K, or BCL2 show exciting activity against aggressive lymphomas and chronic leukemia, but they have little activity against indolent FLs. We speculate that the FL microenvironment protects and sustains the malignant B cells and contributes to FL development, progression, and resistance to therapy. Conversely, we propose that disrupting interactions in the FL niche will be especially effective against FL. Our hypothesis is based on prior work by others and our own work on immune receptor mutations in FL (e.g. TNFSRF14 and EphA7) have revealed cell-cell interactions as key drivers and sustainers of FL biology. My lab has made major contributions to our understanding of the biology and genetics of FL. We built an accurate mouse model of FL and we and others have used this model to interpret the biological function of the most common FL drivers. For example, we reported on the role of epigenetic driver mutations in KMT2D, CREBBP, EZH2, we investigated FL cell metabolism, cell cycle control, aberrant mRNA translation, and the outstanding importance of immune receptors (e.g. TNFSRF14, b2M, EphA7) in FL biology. This work has been reported in an extensive series of high-impact publications. It has also led to several patent filings that protect experimental lymphoma therapies. We now propose a systematic assessment of the cellular composition of the FL microenvironment using cutting edge single-cell RNA sequencing on murine and human FLs. We want to understand how tumor genotype, indolent versus transformed disease stage, and therapy (esp. checkpoint inhibition) shapes the FL niche. We use single cell data to formulate specific hypotheses concerning cell-cell interactions and we use genetic and molecular biology tools to explore underlying mechanisms. Our goal is to identify opportunities to disrupt the supportive niche and to exploit this for new therapies. We have already had some success in this regard, and we engineered bi-functional antibodies and modified CAR-T cells that target interactions between malignant B cells and supportive niche elements. !

针对滤泡性淋巴瘤微环境 滤泡性淋巴瘤（FL）是第二常见的，仍然无法治愈的B细胞淋巴瘤 淋巴瘤FL是一种生长缓慢的癌症，它显示出独特的依赖性， 微环境支持。支持性利基也影响FL疗法。为 例如，BTK、PI3K或BCL 2的抑制剂显示出对抗侵袭性的激动活性， 淋巴瘤和慢性白血病，但它们对惰性FL几乎没有活性。我们 推测FL微环境保护和维持恶性B细胞， 有助于FL的发展、进展和对治疗的抵抗。相反，我们 我认为，破坏FL生态位中的相互作用将特别有效， 花期我们的假设是基于其他人的先前工作和我们自己的免疫工作。 FL中的受体突变（例如TNFSRF14和EphA7）已经揭示了细胞-细胞 相互作用作为FL生物学的关键驱动力和维持者。 我的实验室为我们理解人类的生物学和遗传学做出了重大贡献。 花期我们建立了一个精确的FL小鼠模型，我们和其他人已经使用这个模型来 解释最常见的FL驱动程序的生物功能。比如我们 报告了KMT2D、CREBBP、EZH2中表观遗传驱动突变的作用，我们 研究FL细胞代谢，细胞周期控制，异常mRNA翻译， 免疫受体（如TNFSRF14，b2M，EphA7）在FL中的突出重要性 生物学这项工作已在一系列广泛的高影响力出版物中报道。 它还导致了几项专利申请，保护实验性淋巴瘤疗法。 我们现在提出一个系统的评估细胞组成的FL 使用最先进的单细胞RNA测序对小鼠和人类的微环境 FLS。我们想了解肿瘤基因型，惰性与转化疾病 阶段和治疗（特别是检查点抑制）塑造FL生态位。我们使用单细胞 数据来制定关于细胞间相互作用的具体假设，我们使用 遗传和分子生物学工具来探索潜在的机制。我们的目标是 确定机会，破坏支持利基，并利用这一新的治疗。 我们在这方面已经取得了一些成功，我们设计了双功能 靶向恶性B细胞之间相互作用的抗体和修饰的CAR-T细胞 和支持性的利基元素。 !