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

基质微环境在 B 细胞淋巴瘤进展和免疫逃逸中的作用

• 批准号: 10715434
• 负责人: Leandro C Cerchietti
• 金额: $ 25.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10715434
• 关键词: Address; Administrative Supplement; Adult; Affect; African American; African ancestry; Asian ancestry; Asian population; B-Cell Lymphomas; B-Lymphocytes; Behavior; Biological; Biological Process; Biology; Breast Cancer Patient; Categories; Caucasians; Cells; Characteristics; Classification; Clinical; Cohort Studies; DNA Sequence Alteration; Databases; Demographic Factors; Development; Diagnosis; Disease; Disease Progression; Disparity; Epigenetic Process; European; Exhibits; Extracellular Matrix; Fibroblasts; Flowers; Gene Expression; Genetic; Genomics; Goals; Immune; Immune response; Immunity; Immuno-Chemotherapy; Incidence; Inflammation; Inflammatory; Insurance Coverage; Knowledge; Link; Lymphoma; Lymphoma cell; Malignant Neoplasms; Malignant lymphoid neoplasm; Modernization; Molecular; Mutation; Outcome; Parents; Patients; Phenotype; Population; Prognosis; Race; Research; Research Personnel; Research Project Grants; Role; Rural; Sampling; Socioeconomic Status; Structure of germinal center of lymph node; Subgroup; Therapeutic; Time; Tumor Biology; Western World; Work; activated B cell like; biobank; cancer cell; cancer subtypes; clinically significant; cohort; epigenome; immune cell infiltrate; interest; large cell Diffuse non-Hodgkin' s lymphoma; multi-ethnic; novel; novel therapeutic intervention; outcome disparities; parent grant; prognostic; prognostic value; trait; transcriptomics; treatment response; tumor

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.

项目摘要/摘要 该项目的重点是常见侵略性的弥漫性大B细胞淋巴瘤（DLBCL） 尽管进行了强化化学免疫疗法，但可耐加固率为65％。 DLBCL代表 差异研究的重大临床问题是，它是一种潜在的治愈癌症，但 如果未经治疗或不当治疗，普遍致命。未经治疗的DLBCL患者的预期存活率为<1 一年，而现代标准的化学免疫疗法> 58％的患者还活着并治愈了5年。 参与此行政补充的调查人员的集体工作表明，尽管 DLBCL的高疗法速率，结果仍然异质。实际上，对于非洲的DLBCL患者 祖先的结果明显更糟：在美国，非裔美国人（AA）患者平均被诊断出 年轻10岁，更常见患有早期疾病，总体生存比 他们的白色同行。淋巴恶性肿瘤的这些差异引起了人们对阐明的作用的兴趣 遗传血统影响了人群之间的差异。正如父r01中提出的那样，使用 4,655 DLBCLS的淋巴瘤微环境的转录组分析，我们定义了四个主要淋巴瘤 与不同的生物畸变和临床行为相关的微环境（LME）类别 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种群上，没有或最少 AA患者的代表。但是，关于关于 LME，临床和人口统计学因素与较差的生存有关，包括AA血统，农村地位， 保险状况和社会经济状况。在此补充中，我们将通过探索这些差距来解决这一差距 在AA队列研究中，与LME亚型相对于癌症的基因组改变的关系 细胞。因此，我们提出以下特定目的：特定目的1：阐明LME在中的特征 AA DLBCL患者以及与表观基因组的关系；和特定的目标2：表征CAF和ECM 多民族队列的基因定义的LME DLBCL类别中的表型。我们的建议将解决 AA DLBCL患者中，微环境在生物学和临床结果中的作用首次。我们 将确定种族和祖先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。