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（CLL）是西方世界最常见的白血病。从其多变的临床表现来看，CLL显然不是一种同质性疾病。基因组畸变和突变具有很强的临床影响，但到目前为止，单纯的内在缺陷不能完全解释异质性。来自恶性细胞克隆诱导的微环境的外部因素可能会增加发病机制、临床病程和治疗反应。该研究项目的核心假设是，在CLL中，由基因组变异定义的不同疾病亚组诱导其细胞微环境的不同变化。CLL细胞诱导T细胞功能变化的能力已经得到证实。这些变化确实可能导致一个更适宜的微环境，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组分将在定位、功能及其与CLL细胞的相互作用方面进行表征。由于肿瘤发生中的常见途径在CLL中发生改变（TP 53、ATM、c-MYC、NOTCH信号传导、剪接机制缺陷），因此结果可能转移到其他肿瘤实体。遗传决定的对CLL免疫疗法的抗性的第一个例子是在NOTCH 1突变的CLL病例中，在化疗中加入利妥昔单抗缺乏益处。如果内在缺陷作为潜在机制可以被排除，假设将是CLL细胞和毒性介导效应细胞之间的相互作用受损导致耐药。一般来说，CLL治疗越来越多地朝着靶向，无化疗方案整合环境细胞到作用机制。正在研究的物质是新型单克隆抗体和嵌合抗原受体（汽车），需要功能性效应细胞和补体等因素来诱导肿瘤细胞死亡。此外，B细胞受体信号传导抑制剂、BCL 2抑制剂和免疫调节剂作为CLL的新治疗范例显示出巨大的潜力。所有这些药物目前正在临床试验中进行研究，初步结果显示有希望的疗效和良好的耐受性。然而，越来越明显的是，并非所有疾病亚组都能在相同程度上受益。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会增加抵抗力。我们提出的项目的数据可以提供一个有价值的来源，以快速筛选治疗失败的潜在机制，并找到克服耐药性的治疗策略。

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.