Targeting Plasmacytoid Dendritic Cells to Treat Human Myeloma

描述（由申请人提供）：浆细胞样树突状细胞前体（pDCs）通过TLR7/TLR9感知病毒感染并迅速产生大量1型干扰素（ifn），在抗病毒应答的先天免疫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了pDC在口腔和气道耐受中起关键作用。这与pDCs能够诱导已知具有免疫抑制作用的调节性T细胞（Treg）的发育的发现是一致的。pDCs浸润许多人类肿瘤。在乳腺肿瘤中，pDC浸润与生存率低有关。最近的研究表明，pDC浸润在诱导卵巢癌免疫抑制和促进人多发性骨髓瘤（MM）肿瘤细胞生长、存活和耐药中起关键作用。然而，pDCs在产生和维持免疫耐受以及促进骨髓瘤细胞生长、存活和耐药中的作用的分子机制尚不清楚。我们最近发现了一种pdc特异性受体复合物ILT7/FceR？1 （pDCR）及其配体BST2。通过pDCR的信号传导诱导bcr样信号级联，有效抑制pDCs介导的tlr7 /9介导的1型IFN反应。有趣的是，BST2在骨髓瘤细胞中高表达，提示骨髓瘤细胞可能通过BST2和ILT7的相互作用直接抑制pDCs的先天免疫功能。我们的假设是，人骨髓瘤细胞可能通过BST2/ILT7相互作用抑制pDCs的先天免疫功能，增强骨髓瘤肿瘤微环境中pDCs的耐受性。我们最近制备了BST2单克隆抗体，该抗体可通过抗体介导的细胞毒性直接杀伤骨髓瘤细胞，阻断pDCs的免疫抑制功能，并在TLR9配体激活后促进pDCs的先天免疫功能。我们提出以下目标：目的1将确定人类骨髓瘤浸润性pDCs是否显示BST2/ILT7相互作用诱导的基因和信号特征，并增强诱导免疫耐受的功能；目的2将在骨髓瘤微环境中确定ILT7和BST2相互作用在骨髓瘤诱导的pDCs功能障碍中的作用；最后，Aim 3将开发一种新的策略来重新编程MM中的pDCs，从诱导耐受性到诱导抗病毒样抗肿瘤免疫。这些研究将导致开发新的联合疗法，例如化疗药物加BST2/ILT7阻断抗体，用于治疗骨髓瘤患者；他们也将提高我们对同时免疫靶向MM细胞和pDCs的机制和意义的理解，以恢复免疫系统，最大限度地提高癌症治疗的疗效。

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.