MDSCs in Ovarian Cancer

 描述（由申请人提供）：几十年来，卵巢癌的死亡率基本没有变化。虽然卵巢癌对手术减瘤和铂类药物和紫杉烷类化疗的最初反应通常很好，但耐药癌症通常会复发，患者会死于疾病。不幸的是，大多数被诊断患有卵巢癌的女性都患有晚期癌症，对于这些女性来说，目前的治疗主要是姑息性的，而不是治愈性的。尽管我们尽了最大努力使用目前可用的（主要是传统的）治疗方法，但我们未能改善卵巢癌的长期生存率，因此非常需要从一个新的角度了解卵巢癌患者发生化疗耐药性和肿瘤复发的特定细胞和分子机制。肿瘤微环境由肿瘤细胞、肿瘤起始细胞（或癌症干细胞，CSC）和免疫细胞（例如髓源性抑制细胞，MDSC）组成。CSC被认为在肿瘤的发生、转移和治疗抗性中起关键作用。在卵巢癌中控制CSC自我更新和扩增的机制知之甚少。我们假设免疫抑制细胞（例如MDSC）在调节CSC自我更新和扩增以及控制化疗耐药性和肿瘤复发中起关键作用。我们的初步研究表明，在从卵巢癌患者采集的新鲜肿瘤组织中有显著的MDSC浸润。这些MDSC能够抑制T细胞免疫。卵巢癌相关MDSCs释放一氧化氮（NO）并激活Notch/Bcl信号通路，与化疗耐药相关。此外，MDSC刺激microRNA 101，靶向C-末端结合蛋白-2（CtBP 2）/核心干细胞基因信号通路，影响卵巢癌的干性。因此，免疫抑制机制可能会显著影响卵巢癌生物学和治疗。我们的具体目标是：目的1：验证我们的假设，MDSC影响卵巢癌的干细胞，化疗和结果。目的2：验证MDSC靶向Notch/BCL信号传导并影响癌症化疗耐药性的假设。目的3：验证MDSC靶向microRNA/CtBP 2并影响卵巢癌干性的假设。该提案调查了一种真实的人类疾病，将肿瘤免疫学与肿瘤干细胞生物学、肿瘤生物学和化疗联系起来，并解决了肿瘤免疫抑制与肿瘤环境中癌症干细胞自我更新之间的机制关联，并解决了一个重大的临床问题。该提案具有高度的科学和临床意义，将为该领域的新临床试验铺平道路。

 DESCRIPTION (provided by applicant): 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 and taxanes is often excellent, relapse with drug-resistant cancer usually occurs and patients succumb to their disease. Unfortunately, most women diagnosed with ovarian cancer present with advanced stage cancer, and for these women, current therapy is largely palliative rather than curative. Given our failure to improve long-term survival from ovarian cancer despite our best efforts with currently available (largely conventional) therapies, there is a great need to understand from a novel angle the specific cellular and molecular mechanisms by which chemoresistance occurs and tumor relapses in patients with ovarian cancer. The tumor microenvironment is comprised of tumor cells, tumor initiating cells (or cancer stem cells, CSC), and immune cells (e.g. myeloid derived suppressor cells, MDSC). CSCs are thought to play critical roles in tumor initiation, metastasis and therapeutic resistance. The mechanisms controlling the self-renewal and expansion of CSCs are poorly understood in ovarian cancer. We hypothesized that immunosuppressive cells (e.g. MDSC) play a crucial role in regulating CSC self-renewal and expansion and controlling chemotherapy resistance and tumor relapse. Our preliminary studies have demonstrated significant MDSC infiltration within fresh tumor tissue harvested from patients with ovarian cancer. These MDSCs are able to inhibit T cell immunity. Ovarian cancer associated MDSCs released nitrite oxide (NO) and activated Notch/Bcl signaling pathway, and linked to chemoresistance. Furthermore, MDSCs stimulated microRNA101, targeted C-terminal binding protein-2 (CtBP2)/core stem cell gene signaling pathway and impact ovarian cancer stemness. Thus, an immune suppressive mechanism may significantly impact ovarian cancer biology and therapy. Our specific aims are: Aim 1: To test our hypothesis that MDSCs affect ovarian cancer stemness, chemotherapy and outcome. Aim 2: To test our hypothesis that MDSCs target Notch/BCL signaling and affect cancer chemoresistance. Aim 3: To test our hypothesis that MDSCs target microRNA/CtBP2 and affect ovarian cancer stemness. The proposal investigates a real human disease, links tumor immunology to tumor stem cell biology, tumor biology and chemotherapy, and addresses the mechanistic associations between tumor immune suppression and cancer stem cell self-renewal in the tumor environment, and tackles a significant clinical problem. The proposal is highly scientifically and clinically significant and ill pave the way for novel clinical trials in the field.