A novel role of IGFBP7 in the microenvironment of hepatocellular carcinoma

总结 逃避免疫监视是促进肿瘤发生的重要机制。识别 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， 战略布局致癌性胰岛素样生长因子（IGF）信号被认为是抑制抗肿瘤 肝细胞癌（HCC）免疫监视。然而，在知识上存在差距- 深入了解潜在机制。胰岛素样生长因子结合蛋白-7 在HCC中，IGFBP 7抑制IGF-I信号传导并作为肿瘤抑制因子发挥作用。Igfbp 7敲除 （Igfbp 7-/-）小鼠表现出IGF信号传导的组成性激活，并发生自发性多- 与+/+或+/-小鼠相比，器官肿瘤和显著加速致癌物诱导的HCC。IGFBP7 基质细胞如肝巨噬细胞中的表达显著高于肝细胞， 在Igfbp 7-/-小鼠中，活化的巨噬细胞增加，这表明以前未被认识到的 Igfbp 7在调节肿瘤微环境（TME）中的功能。一个显著的抑制， 免疫监视调节基因的表达和抗原的相应减少 与+/+相比，在Igfbp 7-/-小鼠中观察到树突状细胞的呈递。增加 Igfbp 7-/-小鼠的肿瘤发生与CD 8+和CD 4 + T细胞的肿瘤浸润减少有关。 细胞，而Igfbp 7过表达导致同基因小鼠中小鼠HCC细胞的生长抑制， 依赖于CD 8+和CD 4 + T细胞的存在。这些结果表明IGFBP 7表现出 多效性抗肿瘤活性和免疫应答调节可能是重要的 IGFBP 7的肿瘤抑制功能的组成部分，这是以前没有报道过的。的 我们实验室的长期目标是确定调控HCC的关键参与者，并将其转化为 新的和有效的靶向治疗知识。我们最近的发现强烈暗示了一部小说 IGFBP 7在调节TME和抗肿瘤免疫应答中的作用。我们假设 IGFBP 7缺乏时IGF信号的激活通过增强癌细胞增殖促进HCC 增殖和存活，调节肿瘤-微环境串扰，以及损害肿瘤免疫 监视在治疗上，施用IGFBP 7不仅会抑制癌细胞存活， 还能促进肿瘤的免疫识别，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。圆满完成本 研究将有助于将IGFBP 7过渡到治疗应用，从而帮助挽救数十名 目前尚无有效治疗的HCC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.