Role of extracellular matrix remodeling on high-grade serous ovarian carcinoma immune evasion

这项拟议工作的主要目标是了解缺氧是如何诱导细胞外基质(ECM)的。 卵巢癌的重塑影响免疫逃避。理解这一概念将产生广泛的影响 关于为卵巢癌寻找有效的免疫疗法，卵巢癌是一种特别致命的女性癌症。这个 细胞外基质不仅为肿瘤组织提供结构和生化支持，而且还经历了 直接改变肿瘤微环境的成分和力学性质的重塑 影响免疫逃避机制。考虑到这一点，已经确定缺氧可以影响 肿瘤免疫抑制和这种不足的组织氧或缺氧，促进ECM重塑。然而， 低氧诱导的细胞外基质在免疫逃避和免疫治疗反应中的作用还知之甚少。 卵巢癌患者。 不幸的是，缺乏提供缺氧诱导的细胞外基质重现的临床前模型。 卵巢肿瘤的重塑。因此，能够研究低氧诱导的细胞外基质的新技术 重塑及其对免疫逃避的影响是至关重要的。在导致这一应用的研究中，我们 开发了一种患者衍生的3D组织培养系统，能够概括低氧诱导的ECM和 肿瘤与免疫的相互作用。具体地说，我们将利用工程方法和患者来源的样本 为了评价缺氧诱导的细胞外基质重塑对肿瘤免疫循环的影响，并进一步 验证克服免疫逃避的新疗法。拟议工作的成功完成将使 美国将研究缺氧诱导的细胞外基质重塑在癌症免疫逃避中的作用，以确定如何 肿瘤逃避免疫监视，并确定使癌细胞对免疫重新敏感的新策略 以精确为基础的方式减少肿瘤免疫逃逸的细胞。

The broad goal of the proposed work is to understand how the hypoxia-induced extracellular matrix (ECM) remodeling in ovarian cancer affects immune evasion. Understanding this concept would have a broad impact on identifying effective immunotherapies for ovarian cancer, a particularly deadly form of cancer in women. The ECM not only provides structural and biochemical support to tumor tissue, but also the ECM undergoes remodeling which alters the composition and mechanical properties of the tumor microenvironment, directly influencing immune evasion mechanisms. With this in mind, it has been established that hypoxia can influence tumor immunosuppression and this inadequate tissue oxygen, or hypoxia, promotes ECM remodeling. However, little is known about the role of the hypoxia-induced ECM in immune evasion and response to immunotherapy in ovarian cancer. Unfortunately, there is a scarcity of preclinical models providing recapitulation of the hypoxia-induced ECM remodeling of ovarian tumors. Thus, new technologies that allow the study of the hypoxia-induced ECM remodeling and its impact on immune evasion are crucially required. In studies leading to this application, we developed a patient-derived 3D tissue culture system capable of recapitulating the hypoxia-induced ECM and tumor-immune interactions. Specifically, we will utilize engineering approaches and patient-derived samples in order to assess the effect of the hypoxia-induced ECM remodeling on the tumor-immune cycle and further validate new treatments to overcome immune evasion. Successful completion of the proposed work will allow us to investigate the role of the hypoxia-induced ECM remodeling on cancer immune evasion, to identify how tumors escape immune surveillance, and to ascertain novel strategies to re-sensitize cancer cells to immune cells reducing tumor immune evasion in a precision-based manner.