Macrophage-based ovarian cancer immunotherapy

由于肿瘤微环境中的巨噬细胞可以表现出抗肿瘤或促肿瘤的作用， 调节他们的行为代表了一种潜在的治疗方法。这一点在 卵巢癌进展的背景，其中巨噬细胞是主要的免疫细胞群。虽然这些角色 对NF-κB信号在调节肿瘤相关巨噬细胞中的作用知之甚少，我们有 报道使用多西环素诱导的转基因小鼠特异性增加巨噬细胞内的NF-κB 在体内乳腺或黑色素瘤肿瘤细胞的背景下，模型会导致显著的肿瘤细胞毒性。 我们有证据表明，这些效应既是直接细胞毒能力的结果，也是对其他 免疫细胞。我们已经开始使用卵巢癌的活体模型来深入了解NF-κB在卵巢癌中的作用。 以显著的腹膜肿瘤种植和腹水概括人类疾病的进展 队形。我们的发现使我们相信，直接靶向激活规范的NF-κB活性在 巨噬细胞在卵巢肿瘤进展的特定阶段会诱导细胞毒效应，改善 免疫反应，从而减少肿瘤负荷和腹水积聚。我们将用我们独特的、诱人的 转基因技术证明在卵巢中增加巨噬细胞核因子-κB活性的治疗潜力 癌症进展。这些发现将被用来指导治疗的优化和测试 由脂质体包裹的mtp-PE(临床上用于其他适应症的药物)或IκBα组成 通过纳米颗粒将siRNA特异性地传递给肿瘤相关的巨噬细胞。这两种策略都将 增加巨噬细胞中的核因子-κB信号，限制疾病进展。我们的研究将验证这一假设 肿瘤微环境中巨噬细胞内NF-κB信号的增加限制了肿瘤的进展 并与临床相关的化疗协同作用，因此，代表了一种新的治疗方法。 这些研究将明确增加NF-κB信号的影响，特别是在巨噬细胞 肿瘤微环境与卵巢肿瘤进展的关系，并将显示NF-κB在卵巢癌中的靶向调控 巨噬细胞可以作为一种新的治疗方法。这些临床前研究将为 一种单用或联合化疗改善卵巢功能的新方法 癌症治疗。

As macrophages within the tumor microenvironment can exhibit anti-tumor or pro-tumor effects, modulation of their behavior represents a potential therapeutic approach. This is particularly relevant in the context of ovarian cancer progression where macrophages are a major immune cell population. While the roles of NF-κB signaling in the regulation of tumor-associated macrophages are poorly understood, we have reported that increased NF-κB specifically within macrophages using doxycycline-inducible transgenic mouse models results in significant tumor cell cytotoxicity in the context of mammary or melanoma tumor cells in vivo. We have evidence demonstrating that these effects result from both direct cytotoxic ability and effects on other immune cells. We have begun to gain insights into the roles of NF-κB in ovarian cancer using in vivo models of progression that recapitulate the human disease with significant peritoneal tumor implants and ascites formation. Our findings lead us to believe that direct targeted activation of canonical NF-κB activity in macrophages during defined stages of ovarian tumor progression will induce cytotoxic effects, improve immune responses, and thus decrease tumor load and ascites accumulation. We will use our unique, inducible transgenics to demonstrate the therapeutic potential of increasing macrophage NF-κB activity during ovarian cancer progression. These findings will be used to instruct the optimization and testing of treatments comprised of either liposomally encapsulated MTP-PE (a drug in clinical use for other indications), or of IκBα siRNA delivered specifically to tumor-associated macrophages by nanoparticles. Both of these strategies will increase NF-κB signaling in macrophages and limit disease progression. Our studies will test the hypothesis that increased NF-κB signaling within macrophages in the tumor microenvironment limits tumor progression and synergizes with clinically relevant chemotherapy and thus, represents a novel therapeutic approach. These studies will define the impact of increasing NF-κB signaling specifically in macrophages on the tumor microenvironment and ovarian tumor progression and will show that targeted modulation of NF-κB in macrophages can be harnessed as a novel therapy. These pre-clinical studies will provide critical evidence for a novel immunomodulatory approach alone or combined with relevant chemotherapy for improving ovarian cancer treatment.