Immune Impact on Cancer Chemoresistance

免疫对癌症化疗耐药性的影响

• 批准号: 9207664
• 负责人: WEIPING ZOU
• 金额: $ 60.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207664
• 关键词: Address; Affect; American Society of Clinical Oncology; Antigen-Presenting Cells; Apoptosis; Biochemical; Biological; CD8-Positive T-Lymphocytes; Cancer Patient; Cancer Remission; Carcinoma; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Clinical Trials; Data; Death Rate; Development; Disease; Drug resistance; Environment; Epithelial; FOXP3 gene; Fibroblasts; Fostering; Genetic; Glutathione; Histologic; Human; Immune; Immune Evasion; Immune response; Immune system; Immunotherapy; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Metabolism; Molecular; Mus; Myelogenous; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Ovarian Carcinoma; Ovarian Serous Adenocarcinoma; PDCD1LG1 gene; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Platinum; Play; Publishing; Regimen; Regulation; Regulatory T-Lymphocyte; Relapse; Reporting; Resistance; Resistance development; Role; Serous; Shapes; Stromal Cells; Stromal Neoplasm; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tumor Cell Biology; Tumor Debulking; Tumor Immunity; base; cancer immunotherapy; chemotherapy; clinical application; clinically significant; design; drug development; empowered; human disease; improved; neoplastic cell; novel; patient subsets; receptor; response; tumor; tumor immunology; tumor microenvironment

Death rates attributable to ovarian cancer have been largely unchanged for decades. Although the initial response of ovarian cancer to surgical debulking and chemotherapy with platinum-based drugs is often excellent, relapse with drug-resistant cancer usually occurs and patients succumb to their disease. Patients with ovarian cancer are NOT highly responsive to current immunotherapy including PD-L1 and PD-1 blockade. Platinum-based drugs remain the major and first line chemotherapy for these patients. Thus, there is a great need to understand from a novel angle the specific cellular and molecular mechanisms by which platinum resistance occurs in patients with ovarian cancer. The tumor microenvironment is the primary arena in which tumor cells and the host immune system interact. Characterization of the nature of immune responses in the human cancer microenvironment holds the key to understanding protective tumor immunity and empowering and improving current cancer immunotherapy. Our preliminary data have shown that the interaction between CD8+ T cells and fibroblasts shapes ovarian cancer chemoresistance. Based this novel and surprising finding, we propose that the human cancer microenvironment ALSO holds the key to understanding and reversing the nature of chemoresistance in ovarian cancer. Accordingly, we hypothesize that the cross-talk between T cells, stromal fibroblasts and tumor cells plays an important role in the development of drug resistance. To test this central hypothesis, in this application, we will focus on patients with high-grade serous ovarian carcinoma, which is the most common histologic subtype, and most lethal among epithelial ovarian carcinomas. We will dissect how the interaction between CD8+ T cells and fibroblasts contributes to chemoresistance in patients with ovarian cancer. We have designed 3 relatively independent but mechanistically intertwined aims to test our central hypothesis. Aim 1 is to test our hypothesis that ovarian cancer associated fibroblasts (CAFs) induce platinum resistance through controlling glutathione (GSH) and its metabolites. Aim 2 is to test our hypothesis that the interaction between CD8+ T cells and CAFs affects ovarian cancer chemoresistance. Aim 3 is to explore the molecular mechanisms and evaluate clinical and biological associations between CAFs and CD8+ T cells in ovarian cancer chemoresistance. The proposal investigates a real human disease, links tumor immunology to tumor cell biology, biochemical metabolism and chemotherapy, and addresses their mechanistic and clinical associations in the tumor environment, and tackles a significant clinical problem. The proposal is highly scientifically and clinically significant and will pave the way for novel clinical trials in the field.

数十年来，归因于卵巢癌的死亡率在很大程度上保持不变。虽然最初 卵巢癌对手术缓解和用铂基药物化疗的反应通常是 抗药性癌症的出色复发通常会发生，患者屈服于他们的疾病。患者 卵巢癌对包括PD-L1和PD-1封锁在内的当前免疫疗法的反应不足。 对于这些患者，基于铂的药物仍然是主要和第一线化学疗法。因此，有一个很棒的 需要从新的角度理解铂的特定细胞和分子机制 卵巢癌患者发生抗药性。 肿瘤微环境是肿瘤细胞和宿主免疫系统相互作用的主要领域。 人类癌症微环境中免疫反应性质的表征 了解保护性肿瘤免疫力以及赋权和改善当前癌症的关键 免疫疗法。 我们的初步数据表明，CD8+ T细胞与成纤维细胞之间的相互作用形成了卵巢 癌症化学抗性。基于这个小说和令人惊讶的发现，我们提出了人类癌症 微环境也是理解和逆转化学耐药性质的关键 在卵巢癌中。因此，我们假设T细胞，基质成纤维细胞和 肿瘤细胞在耐药性发展中起重要作用。 为了检验此中心假设，在此应用中，我们将专注于高级浆液卵巢的患者 癌是最常见的组织学亚型，并且在上皮卵巢癌中最致命。 我们将剖析CD8+ T细胞与成纤维细胞之间的相互作用如何有助于化学耐药性 卵巢癌患者。我们设计了3个相对独立但机械上交织的 旨在检验我们的中心假设。 目的1是测试我们的假设，即卵巢癌相关的成纤维细胞（CAF）诱导铂 通过控制谷胱甘肽（GSH）及其代谢产物的抗性。 AIM 2是测试我们的假设，即CD8+ T细胞与CAF之间的相互作用影响卵巢 癌症化学抗性。 AIM 3是探索分子机制并评估临床和生物学关联 在卵巢癌化学耐药的CAF和CD8+ T细胞之间。 该提案研究了一种真实的人类疾病，将肿瘤免疫学与肿瘤细胞生物学联系起来，生化 代谢和化学疗法，并解决了它们在肿瘤中的机械和临床关联 环境，解决一个重大的临床问题。该提案在科学和临床上高度高度 重要的，并将为该领域的新临床试验铺平道路。