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

项目概要/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显示一个数组 基因改变，定义分子亚型，以及对生存微环境的强烈依赖。 我们假设间质微环境的重编程对于hallmark的致瘤性至关重要。 突变介导淋巴瘤进展和免疫逃避。我们建议阐明 淋巴瘤的癌相关成纤维细胞（CAF）和细胞外基质（ECM）成分 微环境来识别治疗漏洞。CAF来源于健康的成纤维细胞， 被癌细胞重新编程为一种新的生物实体。我们的长期目标是治疗性地利用 考虑到遗传定义的DLBCL，重新编程CAF。出于这个原因，关键是要阐明 参与CAF重编程的机制。并不是所有的CAF都以同样的方式重新编程。此外，委员会认为， CAF重编程作为一个转录动态过程，而不是一个终末效应， 建立多种适应性表型。我们的初步数据表明，激活"共享"和 在CAF的重编程中的"私人"途径。我们特别确定并研究了HSF 1的作用， CAF中的"共享"转录因子。没有HSF1的CAFs不能产生具有生物化学活性的ECM。 淋巴瘤进展所需的组成和机械性能。与此同时，缺乏HSF 1在 TME允许建立有效的淋巴瘤免疫应答，导致肿瘤根除。我们 我计划测试我们的中心假设，并通过追求这些特定的目标来实现本申请的目标。 目标：目标1。阐明维持遗传多样性DLBCL的CAF重编程机制： 我们将鉴定遗传性DLBCL亚型中的CAF亚群和ECM组成;并鉴定分子生物学特征。 使用HSF1作为先导效应子，跨CAF亚群和CAF亚群内的通路和重编程因子。目的 2.阐明CAF在使ECM功能化以用于免疫逃避中的作用。我们将描述 生物力学和生物化学的限制CAF有效的淋巴瘤免疫。目标3： 确定靶向CAF在遗传性DLBCL亚型中的治疗影响。康贝特人将以 共靶向CAF和淋巴瘤细胞在分子定义的临床前DLBCL小鼠中的抗淋巴瘤作用 模型我们提出的研究将为间质TME的机制提供重要的见解 重新编程以建立基因定义的DLBCL，并将有助于发展 新的治疗策略集中于靶向这些实体中的基质TME以增加可治愈性。

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.