Hyperthermic Intraperitoneal Chemotherapy Mechanisms in Epithelial Ovarian Cancer

项目摘要 上皮性卵巢癌(EOC)是女性妇科癌症死亡的主要原因，突出了关键 临床需要新的治疗策略。2018年，约有22,000名妇女被诊断为EoC 美国和他们中的大多数人最终会死于他们的疾病。其背后的原因是 存活率低是由于诊断不佳，80%的卵巢癌患者处于晚期(III-IV) 预后较差的原因(5年癌症特异性生存率分别为42%和26%)。高热 腹膜内化疗(HIPEC)是最近出现的一种延长总生存期的临床方案。 对于晚期EOC患者，与标准护理相比，延长了12个月。尽管它被证明是临床上的 对于HIPEC如何延长存活率，人们仍然知之甚少。肿瘤控制的改善是由 是细胞毒作用增强还是肿瘤微环境改变？免疫系统的作用是什么 玩?为了克服这一局限性，我们分析了去卵巢手术时的卵巢肿瘤，并 紧跟在HIPEC协议之后。由于EoC经常被发现转移到大网膜脂肪，我们专注于 这个网站用来询问细胞和分子的变化。我们利用单细胞RNA测序来鉴定 大网膜肿瘤的主要人群以及伴随HIPEC的潜在细胞和分子变化。 我们的数据表明，HIPEC激活免疫细胞并调节上皮细胞和 基质细胞群。同时，我们利用一只小鼠的EoC线开发了一种创新的热疗装置 化疗模式。我们确定高温化疗会增加免疫细胞的渗透。 免疫抑制细胞相应减少。基于这些观察，我们假设 HIPEC的生存益处源于其增强免疫细胞渗透的能力。我们将对此进行测试 利用HIPEC和单细胞创新小鼠模型互补组合的假说 人类患者样本研究的分析。我们提出了两个具体目标。在目标1中，我们将测试 假设HIPEC促进适应性免疫系统的转录激活。在目标2中，我们将测试 假设HIPEC通过减弱免疫抑制来改善EoC。这项研究的目标是获得 有价值的信息进入细胞通路，HIPEC用来干扰EOC进程，以便翻译 将这些发现转化为辅助治疗，以进一步提高HIPEC对以下疾病患者的临床益处 高级EoC。

Project Summary Epithelial ovarian cancer (EOC) is a leading cause of gynecologic cancer death in women, highlighting the critical clinical need for new therapeutic strategies. In 2018 approximately 22,000 women were diagnosed with EOC in the United States and the majority of them will ultimately succumb to their disease. The reason underlying the poor survival is due to poor diagnosis with 80% of patients with EOC present in advanced stage (III-IV) accounting for the poor prognosis (5-year cancer-specific survival 42% and 26%, respectively). Hyperthermic intraperitoneal chemotherapy (HIPEC) has recently emerged as a clinical regimen that prolongs overall survival for patients with advanced EOC by over 12 months compared to standard of care. Despite its proven clinical benefit, how HIPEC extends survival remains poorly understood. Is the improvement in tumor control driven by increased cytotoxic effects or alterations in the tumor microenvironment? What role does the immune system play? To overcome this limitation, we analyzed ovarian tumors at the time of the debulking surgery and immediately following HIPEC protocol. As EOC is often found to metastasize to the omental fat, we focused on this site to interrogate cellular and molecular changes. We leveraged single cell RNA sequencing to identify the major populations in the omental tumors and underlying cellular and molecular changes accompanying HIPEC. Our data demonstrated that HIPEC activates immune cells and modulates the transcriptome of epithelial and stromal cell populations. In parallel, we used a mouse EOC lines to develop an innovative hyperthermic chemotherapy model. We determined that hyperthermic chemotherapy leads to increased immune cell infiltration with a corresponding decrease in immune suppressor cells. Based on these observations, we hypothesize that the survival benefit conferred by HIPEC is due to its ability to augment immune cell infiltration. We will test this hypothesis using a complementary combination with an innovative mouse model of HIPEC and single cell analysis of human patient specimen studies. We propose two Specific Aims. In Aim 1, we will test the hypothesis that HIPEC promotes transcriptional activation of adaptive immune system. In Aim 2, we will test hypothesis that HIPEC via attenuation of immune suppression improves EOC. The goal of the study is to gain valuable information into the cellular pathways that HIPEC uses to disrupt EOC progression in order to translate these findings into adjunct therapies to further enhance the clinical benefit of HIPEC for patients with advanced EOC.