Mechanisms of mature B-cell tumour pathogenesis and of the interplay between host-immunity and these tumours.

在西方国家，非霍奇金淋巴瘤（NHL）的发病率在过去二十年中几乎翻了一番，其中大部分来自成熟的b细胞。虽然改进的诊断和艾滋病相关的淋巴瘤导致了疾病发病率的惊人上升，但这一贡献不超过新病例的50%。在NHL中，活化b细胞弥漫性大b细胞淋巴瘤（ABC-DLBCL）侵袭性最强，临床预后较差。多发性骨髓瘤（MM）是一种源自终末分化成熟b细胞（浆细胞）的肿瘤，是仅次于NHL的第二大常见血液系统恶性肿瘤，尽管近年来化疗取得了进展，但它仍然是一种无法治愈的疾病。存在于这两种肿瘤中的组成性NF-kB活性干扰了化疗的凋亡作用，并可能解释了ABC-DLBCL或MM患者对治疗的不良反应。使用复杂的遗传方法，包括小鼠条件性功能获得和/或功能丧失，我计划在实验环境中开发这些疾病的真正临床前模型，尽可能地再现人类成熟b细胞肿瘤的发生过程。这些模型对于阐明这些恶性肿瘤发病机理的机制因素，并为疾病预防和治疗的进展提供重要信息，应证明是无价的。除了致癌病变外，宿主免疫在肿瘤形成和进展中起着重要作用，这一点越来越清楚。癌症免疫逃逸是一种新兴的“癌症标志”，调节性t细胞（Tregs）可能在此背景下发挥关键作用。然而，尽管Tregs在实体肿瘤中帮助癌症免疫逃逸，但其在血液系统恶性肿瘤中的作用仍然存在争议，因此在试图推断实体肿瘤有效治疗策略时需要谨慎。我计划利用上述疾病的真正小鼠模型，确定Treg细胞在人类ABC-DLBCL和MM的发生和进展中的作用。我希望通过对小鼠与人类肿瘤的物种间肿瘤基因组学比较，能够识别出致病/驱动基因突变，从而作为预后生物标志物和/或治疗靶点。另一方面，更好地了解Treg在血液恶性肿瘤中的功能将为如何以及何时调节其活性以刺激免疫系统来控制肿瘤生长提供见解。

The incidence of non-Hodgkin's lymphoma (NHL), the majority of which derived from mature B-cells, has virtually doubled in the last two decades in westernized countries. Although improved diagnosis, and AIDS associated lymphomas have contributed to this astonishing escalation of disease incidence, this contribution accounts for no more than 50% of the new cases. Amongst NHL's the Activated B-cell Diffuse Large B-cell Lymphoma (ABC-DLBCL) is the most aggressive and with the poorer clinical prognosis. Multiple Myeloma (MM) is a tumour derived from terminally differentiated mature B-cells (plasma cells) and ranks as the second most common haematological malignancy after NHL, and despite recent advances in chemotherapy it is still an incurable disease. Constitutive NF-kB activity, present in both these tumours interferes with the apoptotic effect of chemotherapy and may account for the poor response to treatment of patients with either ABC-DLBCL or MM. Using sophisticated genetic approaches that include conditional gain-of-function and/or loss-of-function in the mouse, I plan to develop bona-fide pre-clinical models of these diseases in an experimental setting that recapitulates human mature B-cell tumourigenesis as closely as currently possible. These models should prove invaluable for the elucidation of the mechanistic factors in the pathogenesis of these malignancies and provide critical information for the advancement of disease prevention and treatment. In addition to oncogenetic lesions, it has become increasingly clear that host immunity plays a fundamental role in tumour formation and progression. Cancer immune escape is an emerging "Hallmark of Cancer" and regulatory T-cells (Tregs) may play a key role in this context. However, although in solid tumours Tregs aid cancer immune escape their role in haematological malignancies remains controversial, warranting caution when attempting to extrapolate effective treatment strategies in solid tumours. I plan to determine the role of Treg cells in the initiation and progression of human ABC-DLBCL and MM, using the bona fide mouse models for these diseases described above. I expect that inter-species comparative oncogenomics of the tumours arising in mice with their human counterparts will lead to the identification of causative/driver genetic mutations, which could function as prognostic biomarkers and/or therapeutic targets. On other hand, a better understanding of Treg function in the context of haematological malignancies will provide insights on how and when to modulate their activity to stimulate the immune system to control tumour growth.