Role of the stromal microenvironment in B-cell lymphoma progression and immune escape

项目总结/摘要 本项目主要研究弥漫性大B细胞淋巴瘤（DLBCL）的生物学特性， 恶性肿瘤的治愈率为65%，尽管加强化学免疫治疗。DLBCL代表一个 差异研究的重要临床问题在于，它是一种潜在的可治愈的癌症，但 如果未经治疗或治疗不当，普遍致命。未经治疗的DLBCL患者的预期生存期<1 在现代标准化学免疫疗法中，>58%的患者存活并在5年内治愈。 参与这一行政补充的调查人员的集体工作表明，尽管 DLBCL的治愈率较高，但结局仍不一致。事实上，对于非洲的DLBCL患者， 祖先的结果明显更糟：在美国，非洲裔美国人（AA）患者平均被诊断为 年龄小于10岁，更常见于晚期疾病，总体生存率低于 他们的白色同伴。淋巴系统恶性肿瘤的这些差异引起了人们对阐明 遗传祖先影响种群间的差异。如父R 01中所建议的，使用 通过对4，655例DLBCL的淋巴瘤微环境进行转录组学分析，我们确定了四种主要淋巴瘤 微环境（LME）类别与不同的生物畸变和临床行为相关 独立于先前描述的基因组DLBCL亚组。所有这些研究，基因组和 转录组学，主要集中在欧洲血统的人群，没有或很少 AA患者的代表。然而，在关于以下方面的关系方面仍然存在知识差距： LME以及与较差生存率相关的临床和人口统计学因素，包括AA血统，农村状况， 保险状况和社会经济状况。在这篇补充文章中，我们将通过探讨这些问题来缩小这一差距。 在一项AA队列研究中，LME亚型与癌症基因组改变的关系 细胞因此，我们提出以下具体目标：具体目标1： AA DLBCL患者及其与表观基因组的关系;以及具体目标2：表征CAF和ECM 多种族队列中遗传学定义的LME DLBCL类别中的表型。我们的提案将解决 首次研究了微环境在AA DLBCL患者的生物学和临床结局中的作用。我们 将确定种族和血统在肿瘤生物学和肿瘤免疫反应中的影响， 非洲血统及其潜在的治疗和预后意义。

PROJECT SUMMARY/ABSTRACT This project focus in the biology of diffuse large B-cell lymphoma (DLBCL) that are common aggressive malignancies with a curability rate of 65% despite intensive chemoimmunotherapy. DLBCL represents a significant clinical problem for disparities research in that it is a potentially curable cancer, but one that is universally fatal if untreated or improperly treated. Untreated DLBCL patients have an expected survival of <1 year, whereas with modern standard chemoimmunotherapy >58% of patients are alive and cured at 5 years. The collective work of investigators involved in this administrative supplement demonstrated that despite the high cure rates for DLBCL, outcomes remain heterogeneous. In fact, for DLBCL patients who are of African ancestry outcomes are significantly worse: in the US, African American (AA) patients were diagnosed on average 10 years younger, more commonly presented with advance stage disease, and had worse overall survival than their white counterparts. These disparities in lymphoid malignancies sparked interest in elucidating the role of genetic ancestry in influencing differences among populations. As proposed in the parent R01, using transcriptomic analysis of the lymphoma microenvironment for 4,655 DLBCLs, we defined four major lymphoma microenvironment (LME) categories that associate with distinct biological aberrations and clinical behavior independently to previously described genomic DLBCL subgroups. All these studies, genomic and transcriptomics, have been focused primarily on populations of European descent, with no or minimal representation of AA patients. However, there remains a gap in knowledge regarding the relationships between the LME and clinical and demographic factors associated with worse survival including AA ancestry, rural status, insurance status, and socio-economic status. In this supplement, we will close this gap by exploring these relationships in an AA cohort study characterizing LME subtypes in relation to genomic alterations in cancer cells. Thus, we propose the following Specific Aims: Specific Aim 1: Elucidate the characteristics of the LME in AA DLBCL patients and the relationship with the epigenome; and Specific Aim 2: Characterize CAF and ECM phenotypes in genetically defined LME DLBCL categories across multiethnic cohort. Our proposal will address for the first time the role of the microenvironment in the biology and clinical outcomes in AA DLBCL patients. We will determine the influence of race and ancestry in tumor biology and tumor immune responses associated with African ancestry and their potential therapeutic and prognostic implications.