Towards targeting the lymphoma microenvironment

以滤泡性淋巴瘤微环境为靶点 滤泡性淋巴瘤(FL)是第二常见且仍无法治愈的B细胞 淋巴瘤。FL是一种生长缓慢的癌症，表现出对一种独特的依赖 支持性的微环境。支持性利基也会影响FL疗法。为 例如，BTK、PI3K或BCL2的抑制剂对攻击性表现出令人兴奋的活性 淋巴瘤和慢性白血病，但它们对懒惰的FLS几乎没有活性。我们 推测FL微环境保护和维持恶性B细胞和 有助于FL的发展、进展和对治疗的抵抗。相反，我们 建议破坏FL利基市场中的互动将特别有效地对抗 佛罗里达州我们的假设是基于别人之前的工作和我们自己在免疫方面的工作 FL中的受体突变(如TNFSRF14和EphA7)揭示了细胞-细胞 互动是外语生物学的关键驱动力和维持者。 我的实验室为我们理解黑色素瘤的生物学和遗传学做出了重大贡献 佛罗里达州我们建立了一个准确的FL小鼠模型，我们和其他人已经使用这个模型 解释最常见的FL驾驶员的生物学功能。例如，我们 表观遗传驱动突变在KMT2D、CREBBP、EZH2、WE中的作用 研究FL细胞的代谢、细胞周期控制、异常的mRNA翻译以及 免疫受体(如TNFSRF14、B2M、EphA7)在FL中的重要作用 生物学。这项工作在一系列影响广泛的高影响力出版物中得到了报道。 它还导致了几项保护实验性淋巴瘤疗法的专利申请。 我们现在建议对FL的细胞组成进行系统的评估 用尖端单细胞RNA测序技术测定小鼠和人的微环境 FLS。我们想了解肿瘤基因、惰性疾病和转化疾病是如何 阶段和治疗(特别是检查点抑制)塑造了FL利基。我们用的是单细胞 数据来阐述关于细胞-细胞相互作用的具体假设，我们使用 基因和分子生物学工具来探索潜在的机制。我们的目标是 找出打破支持性利基的机会，并利用这一机会寻找新的治疗方法。 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。 好了！

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. !