Targeting PP4 to improve ovarian cancer response to immunotherapy

项目摘要/摘要 在所有妇科癌症中，高度恶性浆液性卵巢癌的死亡率最高。有一个 确定新的治疗目标和治疗方法以改善结果的关键未得到满足的需求 适用于化疗耐药的卵巢癌患者。DNA损伤反应(DDR)的缺陷可能会导致 增强肿瘤的免疫原性，从而增强对免疫检查点抑制剂治疗的反应。 PP4是一种多亚单位磷酸酶复合体，在DNA损伤的反应中发挥核心作用 许多在DDR中起关键作用的蛋白质的去磷酸化。然而，PP4在癌症中的作用 发展、化疗耐药和抗肿瘤免疫目前尚不清楚。中心假设是 抑制PP4将使OC细胞对化疗介导的免疫原性敏感，从而增强抗- 肿瘤免疫力，以及对免疫检查点封锁的反应增强。建议的理由是 研究表明，对免疫反应如何被激活以应对PP4缺陷的理解-- 介导的DNA损伤修复有可能转化为新的治疗策略，从而使 卵巢癌患者。这一假设将通过追求以下两个具体目标来检验：1) 确定PP4复合体在OC免疫原性中的作用；以及2)确定PP4在 肿瘤浸润性淋巴细胞的招募、功能和对免疫治疗的反应。在目标1中，PP4的作用 对化疗诱导的免疫原性的基因敲除将通过基因组机制研究进行评估 不稳定性、抗原提呈和免疫原性细胞死亡。在第二个目标下，PP4的作用 缺乏PD-1抑制和化疗将在原代培养的有机类细胞中进行评估 人卵巢癌和两种免疫活性的小鼠卵巢癌模型。机制： 将对炎症信号进行调查。本申请中提出的研究具有创新性，因为它 代表了一种新的理论概念，将重点转移到PP4功能上，将其在抗肿瘤免疫中的作用转移到它的作用上。 这项拟议的研究具有重要意义，因为它预计将促进和扩大我们对 DNA损伤修复解决方案如何有助于抗肿瘤免疫和应答的重要性 免疫疗法。最终，这样的知识有可能为新疗法的开发提供信息。 使多种癌症受益。

PROJECT SUMMARY/ABSTRACT High-grade serous ovarian cancer has the highest mortality rate of all gynecologic cancers. There is a critical unmet need to identify new therapeutic targets and therapeutic approaches that will improve outcomes for women with chemo-resistant ovarian cancer. Deficiencies in the DNA damage response (DDR) can drive increased tumor immunogenicity, which leads to enhanced responses to immune checkpoint inhibitor therapy. PP4 is a multi-subunit phosphatase complex that plays a central role in the response to DNA damage through the dephosphorylation of many proteins that play crucial roles in the DDR. However, the role of PP4 in cancer development, chemoresistance, and anti-tumor immunity is currently unknown. The central hypothesis is that PP4 inhibition will sensitize OC cells to chemotherapy-mediated immunogenicity leading to enhanced anti- tumor immunity, and increased response to immune checkpoint blockade. The rationale for the proposed research is that understanding of the how the immune response is activated in reaction to deficiencies in PP4- mediated DNA damage repair has the potential to translate into new therapeutic strategies that will benefit those with ovarian cancer. This hypothesis will be tested by pursuing the following two specific aims: 1) Determine the role of the PP4 complex in the immunogenicity of OC; and 2) Determine the role of PP4 in tumor-infiltrating lymphocyte recruitment, function, and response to immunotherapy. In Aim 1 the effect of PP4 knockout on chemotherapy-induced immunogenicity will be assessed using mechanistic studies of genomic instability, antigen presentation, and immunogenic cell death. Under the second Aim the effect of PP4 deficiency combined with PD-1 inhibition and chemotherapy will be evaluated in organoid cultures of primary human ovarian cancer and in two immunocompetent mouse models of ovarian cancer. Mechanisms of inflammatory signaling will be investigated. The research proposed in this application is innovative because it represents a new theoretical concept by shifting the focus on PP4 function to its role in anti-tumor immunity. The proposed research is significant because it is predicted to advance and expand our understanding of the importance of how DNA damage repair resolution contributes to anti-tumor immunity and response to immunotherapy. Ultimately, such knowledge has the potential to inform the development of new therapies benefiting many types of cancer.