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: 8450901
• 负责人: EDUARDO M. SOTOMAYOR
• 金额: $ 42.52万
• 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/8450901
• 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; 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.

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抗原呈递给抗原特异性T细胞。然而，这些恶性肿瘤的体内生长通常导致T细胞耐受性的诱导而不是T细胞活化。骨髓来源的抗原呈递细胞（APC）在诱导这种T细胞无反应性状态中起主导作用。重要的是，我们以前已经证明，在体内破坏这些APC介导的致耐受性机制释放了恶性B细胞的内在抗原呈递能力，导致T细胞活化和抗淋巴瘤免疫的发展。因此，有效的抗淋巴瘤免疫的产生具有两个关键要求：（1）BM衍生的APC从非炎性/致耐受性状态转化为炎性/活化状态，和（2）恶性B细胞的抗原呈递细胞功能的增强。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实现。在该提案中，我们将测试以下假设：通过消除恶性B细胞和/或APC中的抗炎机制和/或促进炎症途径来抑制和/或破坏特定组蛋白脱乙酰酶（HDAC），将触发针对套细胞淋巴瘤（MCL）以及侵袭性和不可治愈的非霍奇金淋巴瘤亚型的有效和持久的免疫。为了实现我们的目标，我们将使用特定的分子工具和新型药理学抑制剂的组合，以获得Stat 3信号转导和HDAC 6/HDAC 11在调节B细胞淋巴瘤炎症反应中的作用的机制见解。在小鼠模型（目标1和2）和人MCL细胞（目标3）的体外和体内研究中提出了这个全面的，机械导向的和翻译的项目，我们相信这将导致创新的免疫策略B细胞恶性肿瘤。