Characterization of the immune microenvironment in chronic lymphocytic leukemia with regard to recurrent genomic aberrations and identification of mechanisms of resistance towards novel treatment strategies mediated by the immune microenvironment

慢性淋巴细胞白血病中关于复发性基因组畸变的免疫微环境特征以及免疫微环境介导的新治疗策略耐药机制的鉴定

• 批准号: 253404103
• 负责人: Dr. Jennifer Edelmann, Ph.D.
• 金额: --
• 依托单位: Institute of Cancer
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/253404103?language=en
• 关键词: Characterization; immune; microenvironment; chronic; lymphocytic

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. From its variable clinical behavior it is obvious that CLL is not a homogeneous disease. Genomic aberrations and mutations have strong clinical impact, but up to now intrinsic defects alone cannot explain the heterogeneity to full extent. Extrinsic factors from the microenvironment induced by the malignant cell clone are likely to add on pathogenesis, clinical course and response to treatment. The central hypothesis of the proposed research project is that in CLL distinct disease subgroups defined by genomic variations induce different changes to their cellular microenvironment.Capacity of the CLL cells in general to induce functional changes in T cells has already been demonstrated. Those changes do probably lead to a more hospitable microenvironment with less activity of the host immune system against the malignant clone.Therefore, after a detailed genomic characterization of the sample pool the different cellular components of the tumor microenvironment will be characterized in regard to localization, function and their interaction with the CLL cells. Since common pathways in tumorigenesis are altered in CLL (TP53, ATM, c-MYC, NOTCH signaling, defects in the splicing machinery), transferability of the results to other tumor entities might be possible.Changes in the immune microenvironment are likely to influence response to treatment. A first example of genetically determined resistance to immunotherapy in CLL is the lack of benefit from the addition of Rituximab to chemotherapy in NOTCH1 mutated CLL cases. If intrinsic defects as underlying mechanism can be ruled out, the hypothesis will be that an impaired interaction between CLL cells and the toxicity mediating effector cells causes resistance.In general, CLL treatment is moving more and more towards targeted, chemotherapy-free regimens integrating environmental cells into the mechanism of action. Substances under investigation are novel monoclonal antibodies and chimeric antigen receptors (CARs) requiring functional effector cells and complement among other factors to induce tumor cell death. In addition, inhibitors of B cell receptor signaling, BCL2-inhibitors and immunomodulatoy agents have shown great potential as new treatment paradigms in CLL. All these agents are currently under investigation in clinical trials and first results show promising efficacy combined with favorable tolerability. Nonetheless, it becomes more and more apparent, that not all disease subgroups benefit to the same extent. With an increasing role of therapeutic strategies that implicate environmental immune cells, it is very likely that dysfunctions in the microenvironment add to resistance. The data from our proposed project could provide a valuable source to quickly screen for underlying mechanisms of treatment failure and find therapeutic strategies to overcome resistance.

慢性淋巴细胞白血病(CLL)是西方世界最常见的白血病。从其多变的临床行为来看，CLL显然不是一种同质性疾病。基因组的异常和突变对临床有很强的影响，但到目前为止，仅靠固有缺陷还不能完全解释这种异质性。由恶性细胞克隆诱导的微环境中的外在因素可能会增加发病机制、临床病程和治疗反应。该研究项目的中心假设是，在CLL中，由基因组变异定义的不同疾病亚群会导致其细胞微环境发生不同的变化。CLL细胞总体上诱导T细胞功能变化的能力已经被证明。这些变化可能会导致更适宜的微环境，宿主免疫系统对恶性克隆的活性降低。因此，在对样本池进行详细的基因组表征后，肿瘤微环境的不同细胞成分将从定位、功能及其与CLL细胞的相互作用方面进行表征。由于CLL中肿瘤发生的常见途径(TP53、ATM、c-myc、Noch信号、剪接机制缺陷)发生了改变，因此结果可能会转移到其他肿瘤实体。免疫微环境的变化可能会影响治疗反应。第一个由基因决定的慢性淋巴细胞性白血病免疫治疗耐药性的例子是，在NOTCH1突变的慢性淋巴细胞性白血病病例中，在化疗中加入利妥昔单抗缺乏益处。如果可以排除作为潜在机制的内在缺陷，那么假设是CLL细胞和毒性中介效应细胞之间的相互作用受损导致了耐药性。总的来说，CLL治疗越来越多地朝着靶向的、非化疗的方案发展，将环境细胞整合到作用机制中。正在研究的物质是新型的单抗和嵌合抗原受体(CARS)，需要功能效应细胞和补体等因素来诱导肿瘤细胞死亡。此外，B细胞受体信号转导抑制剂、bcl2-抑制剂和免疫调节剂已显示出巨大的潜力，成为治疗慢性淋巴细胞性白血病的新范式。所有这些药物目前都在临床试验中进行研究，初步结果显示出良好的疗效和良好的耐受性。尽管如此，越来越明显的是，并不是所有的疾病亚组都受益于同样的程度。随着涉及环境免疫细胞的治疗策略的作用越来越大，微环境中的功能障碍很可能增加了耐药性。我们提议的项目的数据可以为快速筛选治疗失败的潜在机制和找到克服耐药性的治疗策略提供有价值的来源。