A novel role of IGFBP7 in the microenvironment of hepatocellular carcinoma

摘要 逃避免疫监视是促进肿瘤发生的重要机制。鉴定 抗肿瘤免疫调节剂的研究将有助于利用这一机制开发有效的治疗方法 战略。癌基因胰岛素样生长因子(IGF)信号被认为可以抑制抗肿瘤作用 肝细胞癌的免疫监测然而，在知识方面存在差距-- 对潜在机制有深入的了解。胰岛素样生长因子结合蛋白-7 胰岛素样生长因子结合蛋白7(IGFBP7)抑制IGF-I信号转导，在肝细胞癌中发挥肿瘤抑制作用。IGFBP7基因敲除 (IGFBP7-/-)小鼠表现出IGF信号的结构性激活和自发的多... 与+/+或+/-小鼠相比，器官肿瘤和明显加速的致癌物诱导的肝癌。IGFBP7 在间质细胞，如肝巨噬细胞，表达显著高于肝细胞， 在IGFBP7-/-小鼠中，活化的巨噬细胞增加，这表明一种以前未被识别的 IGFBP7在调节肿瘤微环境中的作用一个显著的抑制作用 免疫监视调节基因的表达和相应的抗原降低 与+/+相比，在IGFBP7-/-小鼠中观察到树突状细胞的呈递。增加了 IGFBP7-/-小鼠的肿瘤发生与CD8+和CD4+T细胞的肿瘤侵袭减少有关 当IGFBP7过表达导致同基因小鼠小鼠肝癌细胞生长抑制时， 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重要的 IGFBP7的肿瘤抑制功能的组成部分，以前没有报道过。这个 我们实验室的长期目标是确定监管肝细胞癌的关键因素并将其转化为 将知识转化为新颖有效的靶向治疗。我们最近的发现有力地表明了一种新的 IGFBP7在调节TME和抗肿瘤免疫反应中的作用我们假设 IGFBP7缺失时IGF信号的激活通过增强癌细胞促进肝癌的发生 增殖和生存，调节肿瘤-微环境串扰，损害肿瘤免疫 监视系统。在治疗上，给予IGFBP7不仅会抑制癌细胞的存活，而且 还促进对肿瘤的免疫识别，从而更有效地根除肿瘤和 转移瘤。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。圆满完成目前的工作 研究将有助于将IGFBP7转化为治疗应用，从而帮助挽救数十名 目前尚无有效治疗方法的肝细胞癌患者。

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.