Targeting Plasmacytoid Dendritic Cells to Treat Human Myeloma

靶向浆细胞样树突状细胞治疗人骨髓瘤

• 批准号: 8219378
• 负责人: Yong-Jun Liu
• 金额: $ 40.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-29 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8219378
• 关键词: Aftercare; Antibodies; Antigens; Antiviral Response; Blocking Antibodies; Bone Marrow; Cell Death; Cells; Complex; Defect; Dendritic Cells; Development; Disease; Disease Progression; Drug resistance; Equilibrium; Fostering; Functional disorder; Generations; Genes; Human; Immune Tolerance; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; In Vitro; Infiltration; Inflammatory; Interferons; Ligands; Lymphocyte; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Mediating; Molecular; Monoclonal Antibodies; Multiple Myeloma; Natural Immunity; Oral; Pathogenesis; Patients; Pharmaceutical Preparations; Plasma Cells; Play; Production; Reaction; Receptors, Antigen, B-Cell; Refractory; Regulatory T-Lymphocyte; Relapse; Reporting; Role; Series; Signal Transduction; Stromal Cells; TLR7 gene; Time; Treatment Efficacy; Tumor Immunity; Viral; Virus Diseases; acquired immunity; bone; cancer therapy; cell growth; chemotherapy; cytotoxicity; effective therapy; improved; in vivo; innate immune function; killings; macrophage; neoplastic cell; novel; peripheral blood; receptor; response; tumor

DESCRIPTION (provided by applicant): Plasmacytoid dendritic cell precursors (pDCs) play a key role at the interface of innate and acquired immunity in anti-viral responses by sensing viral infection through TLR7/TLR9 and rapidly producing large amounts of type 1 interferons (IFNs). However, several recent studies have also identified pDC as critical players in oral and airway tolerance. This is consistent with the findings that pDCs are capable of inducing development of regulatory T cells (Treg), known to be immunosuppressive. pDCs infiltrate many human tumors. In breast tumors, pDC infiltration is associated with poor survival. More recent studies showed that pDC infiltration plays a critical role in the induction of immune suppression in ovarian cancer and in promoting tumor cell growth, survival and drug resistance in human multiple myeloma (MM). However, the molecular mechanisms underlying the role of pDCs in the generation and maintenance of immune tolerance and in promoting myeloma cell growth, survival and drug resistance are unknown. We have recently identified a pDC-specific receptor complex ILT7/FceR?1 (pDCR) and its ligand BST2. Signaling through pDCR induces a BCR-like signal cascade that potently inhibits TLR7/9-mediated type 1 IFN responses by pDCs. Interestingly, BST2 is highly expressed by myeloma cells, suggesting that myeloma cells may directly inhibit the innate immune function of pDCs via BST2 and ILT7 interaction. Our hypothesis is that human myeloma cells may inhibit the innate immune function of pDCs via BST2/ILT7 interaction and enhance the tolerogenic function of pDCs within the myeloma tumor microenvironment. We recently generated monoclonal antibodies to BST2, which can be used to directly kill myeloma cells by antibody-mediated cytotoxicity, block the immunosuppressive function of pDCs and promote the innate immune function of pDCs when activated by a TLR9 ligand. We propose the following aims: Aim 1 will determine whether human myeloma-infiltrating pDCs display gene and signaling signatures induced by BST2/ILT7 interaction and have enhanced function for inducing immune tolerance; Aim 2 will establish the role of ILT7 and BST2 interaction in myeloma-induced dysfunction of pDCs in the myeloma microenvironment; and finally, Aim 3 will develop a new strategy to reprogram pDCs from inducing tolerance to inducing anti-viral-like anti-tumor immunity in MM. Such studies will result in the development of novel combinational therapies, such as chemotherapy drugs plus BST2/ILT7 blocking antibodies, for the treatment of myeloma patients; they will also improve our understanding of the mechanisms and significance of simultaneously immunotargeting MM cells and pDCs to restore the immune system and maximize the efficacy of cancer treatments. PUBLIC HEALTH RELEVANCE: We hypothesize that human myeloma cells may inhibit the innate immune function of plasmacytoid dendritic cells (pDCs) via BST2/ILT7 interaction and enhance the tolerogenic function of pDCs within the myeloma tumor microenvironment. In this application we proposed a series of in vitro and in vivo studies to examine the potential and mechanism of myeloma-induced inhibition of pDC innate immune responses.

描述（由申请人提供）：浆细胞样树突状细胞前体（pDC）通过TLR7/TLR9感知病毒感染并快速产生大量的1型干扰素（IFN），在抗病毒应答中的先天性和获得性免疫的界面上发挥关键作用。然而，最近的几项研究也确定pDC是口腔和气道耐受性的关键参与者。这与pDC能够诱导已知具有免疫抑制性的调节性T细胞（Treg）的发育的发现一致。pDC浸润许多人肿瘤。在乳腺肿瘤中，pDC浸润与较差的存活率相关。最近的研究表明，pDC浸润在卵巢癌中诱导免疫抑制和在人多发性骨髓瘤（MM）中促进肿瘤细胞生长、存活和耐药性中起关键作用。然而，pDC在产生和维持免疫耐受以及促进骨髓瘤细胞生长、存活和耐药性中的作用的分子机制尚不清楚。我们最近确定了pDC特异性受体复合物ILT7/FceR？1（pDCR）及其配体BST 2.通过pDCR的信号传导诱导BCR样信号级联，其有效地抑制pDC的TLR7/9介导的1型IFN应答。有趣的是，BST2由骨髓瘤细胞高度表达，表明骨髓瘤细胞可以通过BST2和ILT7相互作用直接抑制pDC的先天免疫功能。我们的假设是，人骨髓瘤细胞可能通过BST 2/ILT7相互作用抑制pDC的先天免疫功能，并增强骨髓瘤肿瘤微环境中pDC的致耐受性功能。我们最近产生了针对BST 2的单克隆抗体，其可用于通过抗体介导的细胞毒性直接杀死骨髓瘤细胞，阻断pDC的免疫抑制功能，并在被TLR9配体激活时促进pDC的先天免疫功能。我们提出以下目标：目的1将确定人骨髓瘤浸润pDC是否显示由BST2/ILT7相互作用诱导的基因和信号特征，并具有增强的诱导免疫耐受的功能;目的2将确定ILT7和BST2相互作用在骨髓瘤微环境中骨髓瘤诱导的pDC功能障碍中的作用;最后，目的3：建立一种新的策略，将pDC从诱导免疫耐受重编程为诱导抗病毒样抗肿瘤免疫。这种研究将导致开发新的组合疗法，如化疗药物加BST 2/ILT7阻断抗体，用于治疗骨髓瘤患者;它们还将提高我们对同时免疫靶向MM细胞和pDC以恢复免疫系统和最大化癌症治疗功效的机制和意义的理解。 公共卫生相关性：我们推测，人骨髓瘤细胞可能通过BST 2/ILT7相互作用抑制浆细胞样树突状细胞（pDC）的先天免疫功能，并增强骨髓瘤肿瘤微环境中pDC的致耐受功能。在本申请中，我们提出了一系列体外和体内研究以检查骨髓瘤诱导的pDC先天免疫应答抑制的潜力和机制。