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: 10308482
• 负责人: Leandro C Cerchietti
• 金额: $ 52.91万
• 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/10308482
• 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; Immunosuppression; 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; Translating; Treatment-related toxicity; 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 该项目的重点是常见侵略性的弥漫性大B细胞淋巴瘤（DLBCL） 恶性肿瘤的可耐加工率为65％dospite强化化学免疫疗法。 DLBCL显示一个数组 遗传改变，定义分子亚型，以及对微环境生存的强烈依赖。 我们假设基质微环境的重新编程对于Hallmark的致癌性至关重要 介导淋巴瘤进展和免疫进化的突变。我们建议阐明 淋巴瘤的癌症相关成纤维细胞（CAF）和细胞外基质（ECM）成分 微环境以识别治疗性脆弱性。 CAF源自健康的成纤维细胞 由癌细胞重新编程为一种新型的生物学实体。我们的长期目标是热利用 重新编程的CAF，并考虑了一般定义的DLBCL。因此，阐明至关重要 CAF重编程涉及的机制。并非所有CAF都以相同的方式重新编程。而且， CAF将CAF重新编程为转录动态过程，而不是终端效应，该过程允许 建立各种自适应表型。我们的初步数据表明激活“共享”和 CAF重编程的“私人”途径。我们特别识别并研究了HSF1的作用， CAF中的“共享”转录因子。没有HSF1的CAF无法用生化产生ECM 淋巴瘤进展所需的组成和机械性能。同时，缺乏HSF1 TME允许建立有效的淋巴瘤免疫响应，导致肿瘤洗脱。我们 计划通过追求这些特定 目的：目标1。阐明CAFS的机制重编程，以维持遗传学的DLBCL： 我们将在遗传DLBCL亚型中确定CAFS子人群和ECM组成；并识别分子 使用HSF1作为铅效应子，跨CAFS子人群的途径和重编程因子。目的 2。阐明CAF在使ECM功能化的免疫进化中的作用。我们将表征 CAFS对有效的淋巴瘤免疫施加的生物力学和生化约束。目标3。 确定靶向CAF在遗传DLBCL亚型中的治疗影响。我们将确定 共靶向CAF和淋巴瘤细胞的抗淋巴瘤作用在分子定义的临床前DLBCL鼠中 型号。我们提出的研究将提供有关基质TME机制的重要见解 重新编程以建立一般定义的DLBCL，并将有助于发展 新型热策略的重点是针对这些实体中的基质TME，以提高可加固性。