Immune Impact on Cancer Chemoresistance

几十年来，卵巢癌的死亡率基本没有变化。尽管最初的 卵巢癌对手术减瘤和铂类药物化疗的反应通常 尽管如此，耐药癌症的复发通常会发生，患者屈服于他们的疾病。患者 卵巢癌患者对目前的免疫疗法（包括PD-L1和PD-1阻断）没有高度反应。 铂类药物仍然是这些患者的主要和一线化疗药物。因此， 需要从一个新的角度来理解铂的特定细胞和分子机制， 卵巢癌患者会产生耐药性。 肿瘤微环境是肿瘤细胞与宿主免疫系统相互作用的主要竞技场。 对人类癌症微环境中免疫应答性质的表征， 理解保护性肿瘤免疫以及增强和改善当前癌症的关键 免疫疗法 我们的初步数据表明，CD 8 + T细胞和成纤维细胞之间的相互作用塑造了卵巢癌。 癌症化学抗性。基于这一新颖而令人惊讶的发现，我们提出人类癌症 微环境也是理解和逆转耐药性本质的关键 在卵巢癌中。因此，我们假设T细胞、间质成纤维细胞和间质成纤维细胞之间的相互作用可能是由于T细胞和间质成纤维细胞之间的相互作用引起的。 肿瘤细胞在耐药性的发展中起重要作用。 为了验证这一中心假设，在本申请中，我们将重点关注高级别浆液性卵巢癌患者， 卵巢癌是最常见的组织学亚型，在上皮性卵巢癌中最致命。 我们将剖析CD 8 + T细胞和成纤维细胞之间的相互作用如何促成化疗耐药性。 卵巢癌患者。我们设计了3个相对独立但机械上相互交织的 旨在检验我们的核心假设。 目的1是验证我们的假设，卵巢癌相关成纤维细胞（CAFs）诱导铂 通过控制谷胱甘肽（GSH）及其代谢产物来抵抗。 目的2是验证我们的假设，即CD 8 + T细胞和CAFs之间的相互作用影响卵巢癌的发生。 癌症化学抗性。 目的3：探讨其分子机制，评价其与临床和生物学的关系 CAF和CD 8 + T细胞在卵巢癌化疗耐药中的作用 该提案调查了一种真实的人类疾病，将肿瘤免疫学与肿瘤细胞生物学、生物化学 代谢和化疗，并解决其机制和临床协会在肿瘤 环境，并解决了一个重大的临床问题。该提案具有高度的科学性和临床性 这将为该领域的新型临床试验铺平道路。

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.