A novel role of IGFBP7 in the microenvironment of hepatocellular carcinoma

IGFBP7在肝细胞癌微环境中的新作用

• 批准号: 10410373
• 负责人: DEVANAND SARKAR
• 金额: $ 47.66万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410373
• 关键词: Adult; Antigen Presentation; Antigens; Apoptosis; Binding; Biochemical; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Etiology; Carcinogens; Cell Proliferation; Cell Survival; Cell physiology; Cessation of life; Clinic; Clinical Trials; Data; Dendritic Cells; Diethylnitrosamine; Disease; Environment; Exhibits; Genes; Growth; Hepatocarcinogenesis; Hepatocyte; Immune; Immune Evasion; Immune Targeting; Immune response; Immunocompetent; Immunologic Surveillance; Immunologics; Immunosuppression; Immunotherapeutic agent; Impairment; Incidence; Infiltration; Inflammation; Inflammatory; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Interleukin-6; Knock-out; Knowledge; Kupffer Cells; Laboratories; Liver; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Molecular; Mus; Neoplasm Metastasis; Nivolumab; Nude Mice; Oncogenic; Patients; Phenotype; Play; Preventive; Primary carcinoma of the liver cells; Property; Proteins; Recombinant Insulin-Like Growth Factor; Recombinants; Reporting; Research; Role; Running; Savings; Signal Transduction; Somatomedins; Stromal Cells; System; Testing; Therapeutic; Therapeutic Use Study; Transgenic Mice; Translating; Treatment Efficacy; Tumor Immunity; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; anti-PD-1; anti-tumor immune response; antitumor agent; cancer cell; cell type; effective therapy; feasibility testing; immune activation; immunogenicity; immunoregulation; improved; innovation; insulin-like growth factor binding protein-related protein 1; liver cancer model; macrophage; mortality; mouse model; nanoparticle delivery; neoplastic cell; novel; overexpression; preclinical study; protein function; response; senescence; targeted treatment; therapeutically effective; transcriptome sequencing; tumor; tumor eradication; tumor microenvironment; tumorigenesis; tumorigenic

Summary Evasion from immune surveillance is an important mechanism facilitating tumorigenesis. Identification of regulators of anti-tumor immunity will help exploit this mechanism to develop effective therapeutic strategies. Oncogenic insulin-like growth factor (IGF) signaling is suggested to dampen anti-tumor immune surveillance in hepatocellular carcinoma (HCC). However, there is a gap of knowledge in in- depth understanding of the underlying mechanism. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF-I signaling and functions as a tumor suppressor in HCC. An Igfbp7 knockout (Igfbp7-/-) mouse exhibits constitutive activation of IGF signaling and develops spontaneous multi- organ tumors and markedly accelerated carcinogen-induced HCC compared to +/+ or +/- mice. Igfbp7 expression was significantly higher in stromal cells, such as liver macrophages, versus hepatocytes, and activated macrophages were increased in Igfbp7-/- mice, suggesting a previously unrecognized function of Igfbp7 in modulating the tumor microenvironment (TME). A significant inhibition in expression of immune surveillance regulating genes and a corresponding decrease in antigen presentation by dendritic cells were observed in Igfbp7-/- mice compared to +/+. Increased tumorigenesis in Igfbp7-/- mice was associated with decreased tumor infiltration by CD8+ and CD4+ T cells while Igfbp7-overexpression caused growth inhibition of mouse HCC cells in syngeneic mice, dependent on the presence of CD8+ and CD4+ T cells. These results suggest that IGFBP7 exhibits pleiotropic anti-tumor activities and that modulation of an immune response may be an important component of the tumor suppressor function of IGFBP7, which has not been previously reported. The long-term objectives of our laboratory are to identify key players regulating HCC and translate this knowledge into novel and effective targeted therapies. Our recent findings strongly suggest a novel role of IGFBP7 in regulating the TME and anti-tumor immune response. We hypothesize that activation of IGF signaling in the absence of IGFBP7 promotes HCC by augmenting cancer cell proliferation and survival, modulating tumor-microenvironment crosstalk, and impairing tumor immune surveillance. Therapeutically, administration of IGFBP7 will not only inhibit cancer cell survival, but also promote immune recognition of tumors, resulting in more effective eradication of tumors and metastases. We will perform in-depth molecular, biochemical, immunological, and therapeutic studies using relevant mouse models to establish our hypotheses. Successful completion of the present studies will help transition IGFBP7 to therapeutic application and thereby help save lives of scores of HCC patients for whom no effective therapy currently exists.

概括 逃避免疫监视是促进肿瘤发生的重要机制。鉴别 抗肿瘤免疫调节剂的研究将有助于利用这一机制来开发有效的治疗方法 策略。致癌性胰岛素样生长因子 (IGF) 信号传导可抑制抗肿瘤作用 肝细胞癌（HCC）的免疫监视。然而，在知识方面存在着差距—— 深入了解底层机制。胰岛素样生长因子结合蛋白-7 (IGFBP7) 抑制 IGF-I 信号传导并在 HCC 中充当肿瘤抑制因子。 Igfbp7 敲除 (Igfbp7-/-) 小鼠表现出 IGF 信号的组成型激活并发展出自发的多 与+/+或+/-小鼠相比，器官肿瘤和致癌物诱发的HCC显着加速。免疫球蛋白结合蛋白7 与肝细胞相比，基质细胞（例如肝巨噬细胞）中的表达显着更高， Igfbp7-/- 小鼠中活化的巨噬细胞增加，这表明以前未被识别的 Igfbp7 在调节肿瘤微环境 (TME) 中的功能。显着抑制 免疫监视调节基因的表达和抗原的相应减少 与+/+相比，在Igfbp7-/-小鼠中观察到树突状细胞的呈递。增加 Igfbp7-/- 小鼠的肿瘤发生与 CD8+ 和 CD4+ T 肿瘤浸润减少有关 细胞，而 Igfbp7 过表达导致同基因小鼠 HCC 细胞生长抑制， 依赖于 CD8+ 和 CD4+ T 细胞的存在。这些结果表明 IGFBP7 表现出 多效性抗肿瘤活性和免疫反应的调节可能是一个重要的 IGFBP7 的肿瘤抑制功能的组成部分，此前尚未有报道。这 我们实验室的长期目标是确定调节 HCC 的关键参与者并将其转化为 了解新颖有效的靶向疗法。我们最近的发现强烈暗示了一部小说 IGFBP7 在调节 TME 和抗肿瘤免疫反应中的作用。我们假设 在 IGFBP7 缺失的情况下激活 IGF 信号通过增加癌细胞来促进 HCC 增殖和存活，调节肿瘤微环境串扰，损害肿瘤免疫 监视。在治疗上，施用 IGFBP7 不仅会抑制癌细胞存活，而且 还能促进免疫识别肿瘤，从而更有效地根除肿瘤 转移。我们将进行深入的分子、生化、免疫学和治疗研究 使用相关的小鼠模型来建立我们的假设。顺利完成当前任务 研究将有助于将 IGFBP7 转化为治疗应用，从而帮助挽救数十人的生命 目前尚无有效治疗方法的 HCC 患者。