Epigenetic regulation of T-cell dysfunction in chronic lymphocytic leukemia

描述(申请人提供)：CLL患者面临的问题之一是CLL白血病细胞诱导免疫抑制状态，导致对感染的易感性增加和抗肿瘤免疫反应失败。发展有效的免疫治疗的一个关键障碍是缺乏对CLL免疫功能障碍的分子机制的了解。血液中某些化学物质水平的变化，如IDO酶，可能会导致免疫抑制状态，从而增加感染的易感性，并导致抗肿瘤免疫反应失败。IDO抑制剂已经进入临床舞台，有望恢复CLL患者的免疫功能。我们的中心假设是，CLL白血病细胞通过表观遗传机制诱导免疫抑制途径，如IDO信号，从而逃避T细胞依赖的适应性免疫反应。我们进一步假设，IDO阻断将修复CLL患者功能障碍的T细胞。我们项目的目标是：1)确定CLL患者T细胞功能障碍的表观遗传学机制；2)从研究人员发起的1-甲基-D-色氨酸(1-MT)在复发/难治性CLL患者中的I/II期试验中，确定与IDO抑制剂1-甲基-D-色氨酸(1-MT)临床反应相关的生物标记物。我们将确定导致T细胞功能障碍的基因表达和表观遗传学特征，并确定这些生物标记物是否可以预测接受1-MT治疗的CLL患者的免疫功能改善。这项研究的预期结果是：1)加深了对白血病细胞和CLL患者自体T细胞中IDO通路激活的表观遗传学机制的理解；2)识别了与CLL患者T细胞功能障碍相关的表观遗传生物标记物，以及可以在临床试验中预测1-MT临床反应的生物标记物。这项研究将对未来1-MT在癌症患者中的临床试验产生重大影响。这些结果还将显著提高我们对肿瘤驱动的免疫功能障碍的潜在表观遗传学机制的理解，并将有助于完善现有的癌症免疫治疗策略，并确定新的靶点。由于所有癌症都与免疫缺陷(无能)有关，而且对生物学基础了解甚少，这项研究的结果可能会对癌症生物学和免疫学产生重大的广泛影响。

DESCRIPTION (provided by applicant): One of the problems faced by CLL patients is that CLL leukemic cells induce a state of immunosuppression that causes increased susceptibility to infections and failure of anti-tumor immune responses. A critical barrier to progress in developing effective immunotherapy is the lack of understanding of molecular mechanisms responsible for the immune dysfunction in CLL. Alterations in levels of certain chemicals in the blood, such as the enzyme IDO, can induce a state of immunosuppression that causes increased susceptibility to infections and failure of anti-tumor immune responses. IDO inhibitors have entered the clinical arena with a promise to restore immune functions in CLL patients. Our central hypothesis is that CLL leukemic cells escape T cell dependent, adaptive immune responses by inducing immune suppressive pathways such as IDO signaling through epigenetic mechanisms. We further hypothesize that IDO blockage will repair the dysfunctional T cells in CLL patients. The objectives of our project are: 1) to determine epigenetic mechanisms of T cell dysfunction in CLL; and 2) to identify biomarkers that are associated with clinical response to an IDO inhibitor, 1-Methyl-D- tryptophan (1-MT), in samples collected from an investigator-initiated, open-label, phase I/II trial of 1-MT in relapsed/refractory CLL patients. We will identify gene expression and epigenetic signatures that are responsible for T cell dysfunction and determine if these biomarkers can predict the improved immune functions in CLL patients treated with 1-MT. The expected outcomes from this study are: 1) improved understanding of epigenetic mechanisms involved in activation of the IDO pathway in leukemia cells and autologous T cells from patients with CLL; and 2) identification of epigenetic biomarkers associated with T cell dysfunction in CLL patients as well as biomarkers that can predict the clinical response of 1-MT in clinical trials. The study will have significant impact on future clinical trials of 1-MT in caner patients. The results will also significantly improve our understanding of the underlying epigenetic mechanisms of tumor-driven immune dysfunction, and will aid the refinement of existing cancer immunotherapy strategies and identify novel targets. Because all cancers are associated with immune deficiency (anergy), and because the biological basis is poorly understood, the outcomes of this study are likely to have a significant broad-spectrum impact on cancer biology and immunology.