Targeting PP4 to improve ovarian cancer response to immunotherapy

靶向 PP4 改善卵巢癌对免疫治疗的反应

• 批准号: 10735367
• 负责人: Marion Curtis
• 金额: $ 51.09万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735367
• 关键词: Antigen Presentation; Antigen Presentation Pathway; Binding; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer cell line; Carboplatin; Characteristics; Chemoresistance; Complex; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Repair; Data; Development; Effectiveness; Fatality rate; Frequencies; Gamma-H2AX; Genomic Instability; Human; Immune checkpoint inhibitor; Immune response; Immuno-Chemotherapy; Immunocompetent; Immunotherapy; In Vitro; Individual; Inflammatory; Knock-out; Knowledge; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Natural Killer Cells; Organoids; Phenotype; Phosphoric Monoester Hydrolases; Platinum; Play; Process; Protein Deficiency; Protein Dephosphorylation; Protein Inhibition; Protein phosphatase; Proteins; Reaction; Research; Resolution; Role; STAT1 gene; Serous; Signal Pathway; Signal Transduction; T cell infiltration; T-Lymphocyte; Testing; Therapeutic; Translating; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Woman; anti-tumor immune response; cancer cell; cancer therapy; cancer type; cancer/testis antigen; cell motility; checkpoint therapy; chemotherapy; crosslink; cytotoxicity; drug resistance development; experimental study; immune checkpoint blockade; immunogenic cell death; immunogenicity; improved; improved outcome; in vivo; innovation; knock-down; micronucleus; mortality; mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; overexpression; p53-binding protein 1; phosphoproteomics; programmed cell death protein 1; protein function; protein phosphatase inhibitor-4; recruit; repaired; response; synergism; tumor; tumor growth; tumor microenvironment

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.

项目概要/摘要 高级别浆液性卵巢癌是所有妇科癌症中死亡率最高的。有一个 确定可改善结果的新治疗靶点和治疗方法的关键未满足需求 对于患有化疗耐药性卵巢癌的女性。 DNA 损伤反应 (DDR) 缺陷会导致 肿瘤免疫原性增加，从而增强对免疫检查点抑制剂治疗的反应。 PP4 是一种多亚基磷酸酶复合物，通过以下方式在 DNA 损伤响应中发挥核心作用： 许多在 DDR 中发挥关键作用的蛋白质的去磷酸化。然而，PP4 在癌症中的作用 发育、化疗耐药性和抗肿瘤免疫目前尚不清楚。中心假设是 PP4 抑制将使 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，并增加对免疫检查点封锁的反应。拟议的理由 研究的重点是了解免疫反应如何因 PP4 缺乏而被激活 介导的 DNA 损伤修复有可能转化为新的治疗策略，从而受益 患有卵巢癌的人。该假设将通过追求以下两个具体目标来检验：1) 确定PP4复合物在OC免疫原性中的作用； 2) 确定 PP4 在 肿瘤浸润淋巴细胞的募集、功能和对免疫治疗的反应。在目标 1 中 PP4 的效果 将使用基因组机制研究来评估化疗引起的免疫原性的敲除 不稳定、抗原呈递和免疫原性细胞死亡。第二个Aim下PP4的效果 缺陷与 PD-1 抑制和化疗相结合，将在原代细胞的类器官培养物中进行评估 人类卵巢癌和两种免疫功能正常的卵巢癌小鼠模型。机制 将研究炎症信号传导。本申请中提出的研究具有创新性，因为它 通过将 PP4 功能的焦点转移到其在抗肿瘤免疫中的作用，代表了一个新的理论概念。 拟议的研究意义重大，因为预计它将推进和扩大我们对 DNA 损伤修复解决如何有助于抗肿瘤免疫和反应的重要性 免疫疗法。最终，这些知识有可能为新疗法的开发提供信息 对多种癌症有益。