Targeting Negative Regulatory Pathways for Immunotherapy of B-Cell Lymphomas

针对 B 细胞淋巴瘤免疫治疗的负调控途径

• 批准号: 8013273
• 负责人: EDUARDO M. SOTOMAYOR
• 金额: $ 48.82万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013273
• 关键词: Accounting; Address; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; B lymphoid malignancy; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Bone Marrow; CD4 Positive T Lymphocytes; Cell physiology; Cells; Development; Disease; Generations; Genetic; Goals; Growth; HDAC6 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; Immune; Immune response; Immune system; Immunity; Immunotherapeutic agent; Immunotherapy; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-10; Laboratories; Lymphoid; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Modeling; Molecular; Monoclonal Antibody CD20; Mus; Non-Hodgkin' s Lymphoma; Organ; Pathway interactions; Patients; Play; Process; Production; Recurrence; Regulation; Regulatory Pathway; Relapse; Resistance; Role; Signal Transduction; Specificity; Stat3 Signaling Pathway; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; Tumor-Derived; abstracting; cancer immunotherapy; chemotherapy; cytokine; design; improved; in vivo; inhibitor/antagonist; innovation; insight; killings; mouse model; neoplastic cell; novel; public health relevance; response; tool; tumor

DESCRIPTION (provided by applicant): Abstract B-cell lymphomas, being tumors derived from cells with intrinsic antigen-presenting cell capabilities (B- lymphocytes) can efficiently process and present antigens to antigen-specific T-cell in vitro. However, the in vivo growth of these malignancies usually results in the induction of T-cell tolerance rather than T-cell activation. Bone marrow-derived antigen-presenting cells (APCs) play a dominant role in the induction of this state of T-cell unresponsiveness. Importantly, we have previously demonstrated that in vivo disruption of these APC-mediated tolerogenic mechanisms unleashed the intrinsic antigen-presenting abilities of malignant B-cells resulting in T-cell activation and development of anti-lymphoma immunity. Therefore, generation of an effective anti-lymphoma immunity has two critical requirements: (1) Conversion of BM-derived APCs from a non- inflammatory/tolerogenic status into an inflammatory/activating one, and (2) Augmentation of the antigen- presenting cell function of the malignant B-cell. Both requirements we have found, can be fulfilled by manipulation of intracellular pathways involved in regulation of inflammatory responses. In this proposal we will test the hypothesis that Stat3 inhibition and/or disruption of specific histone deacetylases (HDACs), by abrogating anti-inflammatory mechanisms and/or promoting inflammatory pathways in the malignant B-cells and/or APCs would trigger an effective and long-lasting immunity against Mantle Cell Lymphoma(MCL), and aggressive and incurable subtype of Non-Hodgkin's lymphomas. To achieve our goals, we will use a combination of specific molecular tools and novel pharmacologic inhibitors to gain mechanistic insights into the role of Stat3 signaling and HDAC6/HDAC11 in regulating inflammatory responses in B-cell lymphomas. In vitro and in vivo studies in mouse models (Aims 1 and 2) and in human MCL cells (Aim 3) are proposed within this comprehensive, mechanistically-oriented and translational project that we believe would result in innovative immunotherapeutic strategies for B-cell malignancies. PUBLIC HEALTH RELEVANCE: Mantle cell lymphoma (MCL) is a cancer that arises in lymphoid organs and progresses in the same compartment where important cells of the immune system (T-lymphocytes) are also located, indicating that MCL has developed mechanism(s) to avoid immune attack. Recently, we have identified two intracellular pathways (Stat3 signaling and Histone deacetylases) that impose a significant barrier to our efforts to augment anti-tumor immune responses. The goal of this application is to better understand these barriers and design therapeutic interventions to overcome them and elicit sustained immunity against MCL.

描述（由申请人提供）：摘要B细胞淋巴瘤是源自具有内在抗原呈递细胞能力的细胞（B淋巴细胞）的肿瘤，可以在体外有效地加工抗原并将其呈递给抗原特异性T细胞。然而，这些恶性肿瘤的体内生长通常会导致 T 细胞耐受的诱导，而不是 T 细胞的激活。骨髓源性抗原呈递细胞 (APC) 在诱导这种 T 细胞无反应状态中发挥着主导作用。重要的是，我们之前已经证明，体内破坏这些 APC 介导的耐受性机制可以释放恶性 B 细胞的内在抗原呈递能力，从而导致 T 细胞激活和抗淋巴瘤免疫的发展。因此，产生有效的抗淋巴瘤免疫力有两个关键要求：（1）将骨髓来源的APC从非炎症/耐受状态转化为炎症/激活状态，以及（2）增强抗原呈递细胞恶性B细胞的功能。我们发现，这两个要求都可以通过操纵参与炎症反应调节的细胞内途径来满足。在本提案中，我们将测试以下假设：通过废除抗炎机制和/或促进恶性 B 细胞和/或 APC 中的炎症途径，Stat3 抑制和/或破坏特定组蛋白脱乙酰酶 (HDAC) 将触发有效且有效的治疗。针对套细胞淋巴瘤 (MCL) 和侵袭性且无法治愈的非霍奇金淋巴瘤亚型的持久免疫力。为了实现我们的目标，我们将结合使用特定的分子工具和新型药理学抑制剂，从机制上深入了解 Stat3 信号传导和 HDAC6/HDAC11 在调节 B 细胞淋巴瘤炎症反应中的作用。在这个全面的、以机制为导向的转化项目中提出了小鼠模型（目标 1 和 2）和人类 MCL 细胞（目标 3）的体外和体内研究，我们相信该项目将带来针对 B 细胞恶性肿瘤的创新免疫治疗策略。 公共卫生相关性：套细胞淋巴瘤 (MCL) 是一种起源于淋巴器官的癌症，并在免疫系统重要细胞（T 淋巴细胞）所在的同一区室中进展，表明 MCL 已发展出以下机制：避免免疫攻击。最近，我们发现了两种细胞内途径（Stat3 信号传导和组蛋白脱乙酰酶），它们对我们增强抗肿瘤免疫反应的努力构成了重大障碍。该应用的目标是更好地了解这些障碍并设计治疗干预措施来克服它们并引发针对 MCL 的持续免疫力。