CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival

CD28 介导的多发性骨髓瘤细胞增殖和存活的调节

• 批准号: 7213526
• 负责人: KELVIN P. LEE
• 金额: $ 29.08万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-12 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213526
• 关键词: Antigen-Presenting Cells; Back; Binding; Bone Marrow; CD28 gene; CD80 gene; Cell Communication; Cell Line; Cell Proliferation; Cell Surface Receptors; Cell Survival; Cells; Cellular Immunity; Cessation of life; Chemosensitization; Clinical; Clinical Research; Coculture Techniques; Cytotoxic agent; Data; Dendritic Cells; Dexamethasone; Dioxygenases; Disease Progression; Disease-Free Survival; Elements; Enzymes; Genes; Goals; Immunologics; In Vitro; Ligands; Malignant - descriptor; Mediating; Modeling; Molecular; Multiple Myeloma; Mus; Newly Diagnosed; Patients; Plasma Cells; Play; Receptor Signaling; Regulation; Resistance; Role; Sampling; Selection for Treatments; Serum; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Starvation; Subgroup; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Tryptophan; anergy; cell killing; chemotherapy; crosslink; indoleamine; novel strategies; novel therapeutics; outcome forecast; pressure; receptor; response; therapeutic target

DESCRIPTION (provided by applicant): The interactions between the malignant plasma cells of multiple myeloma (MM) and the bone marrow stroma are essential for myeloma cell proliferation and survival, and play a central role in mediating resistance to chemotherapy. Defining the molecular and cellular elements involved in these interactions has been difficult due to the complexity of the bone marrow microenvironment. Our approach has been to identify cell surface receptors that are characteristically expressed on myeloma cells, and then identify cells that express the ligands for these receptors. We have focused on the costimulatory receptor CD28, which is expressed predominantly on T cells but also on normal plasma cells and myeloma cells. For T cells, CD28 is activated upon binding to CD80 (B7-1) and CD86 (B7-2) expressed on antigen presenting cells (especially dendritic cells (DC)), and in conjunction with T cell receptor signaling significantly augments T cell proliferation, effector function and survival. In contrast to T cells, little is known about the function of CD28 in plasma/myeloma cells. However, clinical studies have demonstrated a highly significant correlation between myeloma disease progression and myeloma cell CD28 expression, and MM CD28 expression as a significant predictor of shortened disease-free survival in newly diagnosed patients. These clinical observations implicate an important contribution of CD28 to myeloma cell survival, particularly under chemotherapy treatment selection pressure. Our preliminary studies demonstrate that direct activation of myeloma cell CD28 induces activation of NF?B, downregulates MM cell proliferation and protects against serum starvation and dexamethasone-induced death. Coculture with dendritic cells (DC) expressing CD80/CD86 also elicits CD28-mediated effects on MM survival and proliferation. Furthermore, we have found that CD28+/CD86+ myeloma cell lines express indoleamine 2, 3 dioxygenase (IDO), a tryptophan-catabolizing enzyme that has been previously shown to be induced by B7 crosslinking in DC to mediate T cell anergy/unresponsiveness. We hypothesize that myeloma CD28 transduces survival signals through downstream activation of NF?B, and that MM CD28 is activated by a cell-cell interaction with DC (and/or other CD86+ myeloma cells) located in the bone marrow. Furthermore, "back" signaling through B7 (on the myeloma cell or DC) induces IDO and contributes to the suppression of cell-mediated immunity characteristically seen in MM patients. The Aims of this application are 1). Define the molecular components of CD28 activation in myeloma cells, 2). Characterize the cellular responses to CD28 activation, 3). Define the cellular partners that activate myeloma CD28, 4).Assess if targeting myeloma CD28 itself, components of its signaling pathway or stromal partners can be exploited therapeutically. These studies may provide novel strategies for the treatment of multiple myeloma.

描述（申请人提供）：多发性骨髓瘤（MM）恶性浆细胞与骨髓间质之间的相互作用是骨髓瘤细胞增殖和存活的必要条件，并在介导化疗耐药中起核心作用。由于骨髓微环境的复杂性，确定参与这些相互作用的分子和细胞因素一直很困难。我们的方法是鉴定在骨髓瘤细胞上特征性表达的细胞表面受体，然后鉴定表达这些受体配体的细胞。我们主要关注共刺激受体CD28，它主要在T细胞上表达，但也在正常浆细胞和骨髓瘤细胞上表达。对于T细胞，CD28在与抗原提呈细胞（特别是树突状细胞（DC））上表达的CD80 （B7-1）和CD86 （B7-2）结合后被激活，并与T细胞受体信号一起显著增强T细胞的增殖、效应功能和存活。与T细胞不同，我们对CD28在浆细胞/骨髓瘤细胞中的功能知之甚少。然而，临床研究表明骨髓瘤疾病进展与骨髓瘤细胞CD28表达高度相关，而MM CD28表达是新诊断患者无病生存期缩短的重要预测因子。这些临床观察暗示CD28对骨髓瘤细胞存活的重要贡献，特别是在化疗选择压力下。我们的初步研究表明，直接激活骨髓瘤细胞CD28可诱导NF？B，下调MM细胞增殖，保护血清饥饿和地塞米松诱导的死亡。与表达CD80/CD86的树突状细胞（DC）共培养也能引起cd28介导的对MM存活和增殖的影响。此外，我们发现CD28+/CD86+骨髓瘤细胞系表达吲哚胺2,3双加氧酶（IDO），这是一种色氨酸分解酶，先前已被证明是由DC中的B7交联诱导的，以介导T细胞的能量/无反应性。我们假设骨髓瘤CD28通过下游NF？B，并且MM CD28通过与位于骨髓中的DC（和/或其他CD86+骨髓瘤细胞）的细胞间相互作用被激活。此外，通过B7（在骨髓瘤细胞或DC上）的“反向”信号诱导IDO，并有助于抑制MM患者特有的细胞介导的免疫。这个应用程序的目的是1)。定义骨髓瘤细胞中CD28激活的分子成分，2)。表征细胞对CD28激活的反应，3)。确定激活骨髓瘤cd28,4的细胞伴侣。评估是否靶向骨髓瘤CD28本身，其信号通路成分或基质伴侣可以用于治疗。这些研究可能为多发性骨髓瘤的治疗提供新的策略。