Immune Impact on Cancer Chemoresistance

可归因于卵巢癌的死亡率几十年来基本没有变化。虽然最初的 卵巢癌对手术切除和以铂为基础的药物化疗的反应 很好，耐药癌症的复发通常会发生，患者会屈服于他们的疾病。病人 卵巢癌患者对目前的免疫治疗包括PD-L1和PD-1阻断反应不高。 铂类药物仍然是这些患者的主要和一线化疗药物。因此，有一个很大的 需要从一个新的角度来理解铂 卵巢癌患者会出现耐药性。 肿瘤微环境是肿瘤细胞与宿主免疫系统相互作用的主要场所。 对人类癌症微环境中免疫反应的性质的表征 理解肿瘤保护性免疫和赋能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细胞和成纤维细胞之间的相互作用形成了卵巢 癌症化疗耐药性。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化疗耐药本质的关键 卵巢癌患者。因此，我们假设T细胞、间质成纤维细胞和 肿瘤细胞在肿瘤耐药的形成中起着重要作用。 为了验证这一中心假设，在本应用程序中，我们将重点关注高级别浆液性卵巢癌患者 癌是最常见的组织亚型，也是上皮性卵巢癌中最致命的。 我们将剖析CD8+T细胞和成纤维细胞之间的相互作用是如何促进化疗耐药的。 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(CAF)产生铂 通过控制谷胱甘肽(GSH)及其代谢物的抗性。 目标2是验证我们的假设，CD8+T细胞和CAF之间的相互作用影响卵巢 癌症化疗耐药性。 目标3是探索分子机制并评估临床和生物学联系。 CAF和CD8+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、生化 代谢和化疗，并阐述了它们在肿瘤中的机制和临床联系 并解决了一个重要的临床问题。这项建议具有很高的科学性和临床应用价值。 具有重要意义，并将为该领域的新临床试验铺平道路。

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.