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: 9913295
• 负责人: Leandro C Cerchietti
• 金额: $ 57.53万
• 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/9913295
• 关键词: Apoptosis; B-Cell Lymphomas; Biochemical; Biological; Biology; Biomechanics; Cells; Data; Dependence; Development; Event; Extracellular Matrix; Fibroblasts; Generations; Genetic; Genetic Transcription; Genotype; Goals; Growth; HSF1; Immune; Immune Evasion; Immune response; Immunity; Immuno-Chemotherapy; In Vitro; Infiltration; Knockout Mice; Lead; Lymphoma; Lymphoma cell; Malignant Neoplasms; Mediating; Mesenchymal; Molecular; Mus; Mutation; Oncogenic; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Population; Privatization; Process; Regulatory T-Lymphocyte; Research; Role; Solid Neoplasm; Spontaneous Remission; Stromal Neoplasm; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Translating; cancer cell; heat-shock factor 1; human disease; implantation; insight; large cell Diffuse non-Hodgkin' s lymphoma; mechanical properties; molecular subtypes; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prognostic value; supportive environment; trait; transcription factor; transcriptomics; tumor; tumor eradication; tumor growth; tumor microenvironment

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. DLBCLs display an array of genetic alterations, that define molecular subtypes, and strong dependence on the microenvironment for survival. We hypothesize that reprogramming of the stromal microenvironment is critical for the oncogenicity of hallmark mutations that mediate lymphoma progression and immune evasion. We propose to elucidate the roles of the cancer-associated fibroblasts (CAF) and extracellular matrix (ECM) components of the lymphoma microenvironment to identify therapeutic vulnerabilities. CAFs are derived from healthy fibroblasts that have been reprogrammed by cancer cells into a novel biological entity. Our long-term goal is to therapeutically exploit reprogrammed CAFs with consideration of genetically-defined DLBCLs. For this reason, it is critical to elucidate the mechanisms involved in CAF reprogramming. Not all CAFs are reprogrammed in the same way. Moreover, rather than a terminal effect, CAF reprogramming as a transcriptionally dynamic process that allows the establishment of a variety of adaptive phenotypes. Our preliminary data suggest the activation of “shared” and “private” pathways in the reprogramming of CAFs. We specifically identify and studied the role of HSF1, one of the “shared” transcription factors in CAFs. CAFs without HSF1 failed to produce an ECM with the biochemical composition and mechanical properties required for lymphoma progression. Concomitantly, lack of HSF1 in the TME allowed the establishment of an effective lymphoma immune response leading to tumor eradication. We plan to test our central hypothesis and accomplish the objective of this application by pursuing these specific aims: Aim 1. Elucidate mechanisms of CAFs reprogramming that sustain genetically diverse DLBCLs: We will identify CAFs sub-populations and ECM composition in genetic DLBCL subtypes; and identify molecular pathways and reprogramming factors across and within CAFs sub-populations using HSF1 as lead effector. Aim 2. Elucidate the role of CAFs in functionalizing the ECM for immune evasion. We will characterize biomechanical and biochemical constraints imposed by CAFs to an effective lymphoma immunity. Aim 3. Determine the therapeutic impact of targeting CAFs in genetic DLBCL subtypes. We will determine the anti-lymphoma effect of co-targeting CAFs and lymphoma cells in molecularly-defined pre-clinical DLBCL murine models. The studies that we propose will provide significant insights on the mechanisms of stromal TME reprogramming for the establishment of genetically defined DLBCLs and will contribute towards development of novel therapeutic strategies focused on targeting the stromal TME in these entities to increase curability.

项目摘要/摘要 本项目主要研究常见侵袭性弥漫性大B细胞淋巴瘤(DLBCL)的生物学特性 尽管进行了密集的化学免疫治疗，恶性肿瘤的治愈率仍为65%。DLBCL显示一组 定义分子亚型的基因改变，以及对生存微环境的强烈依赖。 我们假设间质微环境的重新编程对HARMARK的致瘤性至关重要。 介导淋巴瘤进展和免疫逃避的突变。我们建议澄清 淋巴瘤的癌相关成纤维细胞(CAF)和细胞外基质(ECM)成分 微环境，以确定治疗的脆弱性。CAF来自健康的成纤维细胞，这些细胞已经 被癌细胞重新编程为一种新的生物实体。我们的长期目标是在治疗上利用 考虑到遗传定义的DLBCL，对CAF进行了重新编程。出于这个原因，澄清是至关重要的 CAF重新编程所涉及的机制。并不是所有的CAF都以相同的方式重新编程。此外， 而不是终端效应，CAF重新编程为转录动态过程，允许 建立多种适应性表型。我们的初步数据显示，“共享”和 CAF重新编程中的“私人”途径。我们专门识别和研究了HSF1的作用，HSF1是 CAF中的“共享”转录因子。没有HSF1的CAF无法产生具有生化的ECM 淋巴瘤进展所需的成分和机械性能。随之而来的是，在 TME允许建立有效的淋巴瘤免疫反应，从而导致肿瘤根除。我们 计划测试我们的中心假设，并通过追求以下具体目标来实现此应用程序的目标 目的：目的1.阐明维持遗传多样性DLBCL的CAF重编程机制： 我们将确定遗传DLBCL亚型中的CAF亚群和ECM组成；并确定分子 使用HSF1作为主要效应器的CAF亚群之间和内部的通路和重新编程因子。目标 2.阐明CAF在ECM免疫逃逸中的作用。我们将描述 CAF对淋巴瘤有效免疫的生物力学和生化约束。目标3. 确定靶向CAF对遗传性DLBCL亚型的治疗效果。我们将确定 CAF与淋巴瘤细胞共靶向对DLBCL小鼠的抗淋巴瘤作用 模特们。我们提出的研究将对间质TME的机制提供重要的见解 重新编程以建立遗传定义的DLBCL，并将有助于制定 新的治疗策略侧重于靶向这些实体的间质TME，以提高治愈率。