MDSCs in Ovarian Cancer

 描述(申请人提供)：可归因于卵巢癌的死亡率几十年来基本没有变化。虽然卵巢癌对手术切除和铂类药物和紫杉烷类药物化疗的初始反应通常很好，但耐药癌症的复发通常会发生，患者会屈服于他们的疾病。不幸的是，大多数被诊断为卵巢癌的女性都患有晚期癌症，对这些女性来说，目前的治疗主要是姑息治疗，而不是根治。尽管我们目前已尽了最大努力(主要是传统疗法)，但仍未能提高卵巢癌患者的长期生存率，因此有必要从新的角度了解卵巢癌患者化疗耐药发生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(或肿瘤干细胞，CSC)和免疫细胞(如髓系抑制细胞，MDSC)组成。肿瘤干细胞被认为在肿瘤的发生、转移和治疗耐药中起关键作用。在卵巢癌中，控制CSCs自我更新和扩张的机制知之甚少。我们推测，免疫抑制细胞(如MDSC)在调节CSC的自我更新和扩增、控制化疗耐药和肿瘤复发方面发挥着关键作用。我们的初步研究表明，从卵巢癌患者的新鲜肿瘤组织中提取的MDSC具有显著的侵袭作用。这些MDSCs能够抑制T细胞免疫。卵巢癌相关MDSCs释放亚硝酸盐(NO)，激活Notch/Bcl信号通路，与化疗耐药有关。此外，MDSCs还激活了microRNA101、靶向C末端结合蛋白-2(CtBP2)/核心干细胞基因的信号通路，并影响卵巢癌的干细胞分化。因此，免疫抑制机制可能会对卵巢癌的生物学和治疗产生重大影响。我们的具体目标是：目标1：验证我们的假设，即MDSCs影响卵巢癌的干细胞、化疗和预后。目的2：验证MDSCs靶向Notch/BCL信号通路并影响肿瘤化疗耐药的假说。目的3：验证MDSCs靶向microRNA/CtBP2并影响卵巢癌干细胞分化的假设。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，解决了肿瘤环境中肿瘤免疫抑制和癌症干细胞自我更新之间的机制关联，并解决了一个重要的临床问题。这项提议具有高度的科学和临床意义，并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.