Matrix metalloproteinase-2 modulates inflammation via TLR2

基质金属蛋白酶-2 通过 TLR2 调节炎症

• 批准号: 8874174
• 负责人: Nina Bhardwaj
• 金额: $ 35.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874174
• 关键词: Animal Model; Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Line; Cell physiology; Cells; Clinical; Clinical Trials; Data; Dendritic Cells; Diagnostic Neoplasm Staging; Disseminated Malignant Neoplasm; Exhibits; Exposure to; Extracellular Matrix; Failure; Gelatinase A; Gelatinases; Genetic Transcription; Granzyme; Growth; Health; Heating; Human; IFNAR1 gene; Immune; Immune response; Immune system; Immunity; Immunotherapy; In Vitro; Indium; Inflammation; Inflammatory; Interferons; Interleukin-12; Interleukin-13; Interleukin-2; Interleukin-4; Lead; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Melanoma Cell; Memory; Metalloproteases; Metastatic Melanoma; Molecular Conformation; Normal tissue morphology; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Phosphorylation; Physiological; Production; Proteins; Receptor Signaling; Role; STAT1 gene; Signal Pathway; Signal Transduction; Specificity; Staging; Stromal Cells; T-Lymphocyte; TLR2 gene; TNF gene; TNFSF4 gene; Testing; Tumor Antigens; Tumor Cell Biology; Tumor Cell Invasion; Tumor Immunity; Tumor stage; Tumor-Infiltrating Lymphocytes; Up-Regulation; adaptive immunity; angiogenesis; base; cell motility; clinically relevant; cohort; collagenase; cytokine; extracellular; in vivo; interleukin-12 subunit p35; melanoma; mouse model; neoplastic cell; novel; outcome forecast; receptor; response; success; targeted cancer therapy; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; type I interferon receptor

DESCRIPTION (provided by applicant): Immune therapies have had some success in the treatment of metastatic cancers. However, durable effects are limited in most patients despite the accumulation of intra-tumoral antigen-specific T cells. The tumor microenvironment (TME) is partly responsible for these failures through active blockade of local antitumor immune responses and facilitation of immune escape. Several immune modulating factors and/or cells are elicited within the TME, including the metalloproteinases, which enhance tumor growth and invasion through effects upon the tumor stroma, vasculature, and activation of factors such as TGF� and TNF�. Matrix metalloproteinase-2 (MMP-2), a gelatinase, is over-expressed in most cancers including melanoma, and its expression is associated with increased dissemination and poorer survival/prognosis. We recently found that enzymatically active MMP-2-conditioned dendritic cells (DCs) preferentially generate TH2 cells through mechanisms that inhibit IL-12 and up-regulate OX40L expression. Of note, only enzymatically active MMP-2 blocks IL-12 production, while both active and inactive conformations of MMP-2 induce up-regulation of OX40L. Strikingly, we also detected TILs in several patients that displayed MMP-2-specific responses. These responses were TH2-like and their presence was found to be inversely correlated with survival. MMP-2, therefore, acts simultaneously as an endogenous TH2 "conditioner" and tumor-associated antigen, which may explain, in part, the occurrence of unfavorable TH2 responses in melanoma. We previously characterized the mechanism responsible for IL-12 inhibition, which involves enzymatic cleavage of the type IIFN receptor, and consequent reduced STAT-1 phosphorylation and IL-12p35 transcription. We have since identified other novel immune mechanisms underlying MMP-2-dysregulation of DCs and the TME: MMP-2 directly triggers TLR-2 mediated signaling on both DCs and melanoma cell lines, inducing expression of OX40L and production of pro-inflammatory cytokines, respectively. In Aim1, therefore, we will first identify the relevant TLR receptors and signaling pathways involved in OX40L up-regulation. The clinical relevance of this novel finding will be tested in animal models of melanoma (Aim 2). Finally, in Aim 3, we will evaluate whether MMP-2 directly modulates melanoma function and growth via TLR-mediated pathways.

描述（由申请人提供）：免疫疗法在治疗转移性癌症方面取得了一些成功。然而，尽管肿瘤内抗原特异性T细胞的积累，但在大多数患者中的持久效果是有限的。肿瘤微环境（TME）通过主动阻断局部抗肿瘤免疫应答和促进免疫逃逸，部分负责这些失败。在TME内引发几种免疫调节因子和/或细胞，包括金属蛋白酶，其通过对肿瘤基质、脉管系统的作用以及诸如TGF β和TNF β的因子的活化来增强肿瘤生长和侵袭。 基质金属蛋白酶-2（MMP-2）是一种明胶酶，在包括黑色素瘤在内的大多数癌症中过度表达，其表达与播散增加和生存/预后较差相关。我们最近发现，酶活性MMP-2条件树突状细胞（DC）优先产生TH 2细胞通过抑制IL-12和上调OX 40 L表达的机制。值得注意的是，只有酶活性MMP-2阻断IL-12的产生，而MMP-2的活性和非活性构象都诱导OX 40 L的上调。引人注目的是，我们还在几个显示MMP-2特异性反应的患者中检测到TILs。这些反应是TH 2样的，并且发现它们的存在与存活率呈负相关。因此，MMP-2同时作为内源性TH 2“调节剂”和肿瘤相关抗原，这可以部分解释黑色素瘤中不利的TH 2应答的发生。我们先前表征了负责IL-12抑制的机制，其涉及IIFN型受体的酶促裂解，以及随后降低的STAT-1磷酸化和IL-12 p35转录。此后，我们已经确定了其他新的免疫机制，这些机制是MMP-2-DCs和TME失调的基础：MMP-2直接触发DCs和黑素瘤细胞系上TLR-2介导的信号传导，分别诱导OX 40 L的表达和促炎细胞因子的产生。因此，在Aim 1中，我们将首先确定参与OX 40 L上调的相关TLR受体和信号通路。将在黑色素瘤动物模型中测试这一新发现的临床相关性（目的2）。最后，在目标3中，我们将评估MMP-2是否通过TLR介导的途径直接调节黑色素瘤的功能和生长。