Role of PI3Kinase in Tumor Progression and Metastasis

实体瘤的特点是有大量促进肿瘤的炎性浸润物，包括 主要是免疫抑制的巨噬细胞、单核细胞和粒细胞。这些免疫抑制细胞 阻止T细胞在肿瘤微环境中的募集和/或激活，促进肿瘤血管生成 和转移。年，美国约有170万新癌症病例被诊断出来 2016年，仅2016年就有60万患者死于癌症，迫切需要推进研究 探讨免疫抑制髓系细胞促进肿瘤进展的机制 开发可以针对这些免疫抑制细胞的新疗法。 我们最近发现，PI(3)激酶γ控制着免疫刺激和免疫之间的关键开关 炎症和癌症期间的抑制作用。我们发现PI3Kγ既能促进髓系细胞募集，又能促进 肿瘤中的免疫抑制极化。PI3Kγ信号通过mTOR和Akt诱导免疫 抑制T细胞激活的转录抑制程序。相比之下，选择性停用 巨噬细胞PI3Kγ刺激核因子κB和Tbk1，从而促进免疫刺激转录程序 刺激CD8+T细胞活化和抗肿瘤细胞毒作用。PI3Kγ对肿瘤再极化的抑制作用 联合巨噬细胞与抗PD-1检查点抑制物协同治疗促肿瘤作用 在癌症小鼠模型中清除以及持久的免疫抗肿瘤记忆。此外，我们 发现PI3Kγ导向的抗炎基因表达标志预示着肺内存活率较低， 乳腺癌、胃癌和头颈癌患者。由于我们的发现，PI3Kγ抑制剂已经进入 加州大学圣迭戈分校和其他地方的实体肿瘤临床试验。 在这些拟议的研究中，我们将评估pi3kγ在肿瘤中发挥重要作用的前提。 调控控制髓系细胞的关键信号转导和转录通路的进展 贩运和两极分化。我们将描述髓系细胞的详细分子机制 PI3Kγ调控肿瘤进展。我们假设，对分子事件的精确理解 哪种PI3Kγ调节肿瘤进展将使我们能够开发治疗这些疾病的新疗法 疾病。这项提议的具体目的是：1)确定PI3Kγ的分子机制 在体内外调节巨噬细胞/髓系细胞的极性和免疫反应；2)确定如何 PI3Kγ！调节免疫抑制髓系细胞在肿瘤中的积聚并开发抑制其 以及3)确定抑制PI3Kγ与癌症治疗药物协同作用的机制 抑制肿瘤进展。 好了！

Solid tumors are characterized by an abundant, tumor-promoting inflammatory infiltrate that is comprised largely of immune suppressive macrophages, monocytes and granulocytes. These immune suppressive cells prevent T cell recruitment and/or activation in the tumor microenvironment and stimulate tumor angiogenesis and metastasis. As approximately 1,700,000 new cases of cancer will be diagnosed in the United States in 2016, and 600,000 patients will die from cancer in 2016 alone, there is a pressing need to advance research into the mechanisms by which immune suppressive myeloid cells promote tumor progression to enable the development of novel therapeutics that can target these immune suppressive cells. We recently found that PI(3)Kinase γ controls a critical switch between immune stimulation and immune suppression during inflammation and cancer. We found that PI3Kγ promotes both myeloid cell recruitment and immune suppressive polarization in tumors. PI3Kγ signals through mTor and Akt to induce an immune suppressive transcriptional program that inhibits T cell activation. In contrast, selective inactivation of macrophage PI3Kγ stimulates NFκB and TBK1, thus promoting an immunostimulatory transcriptional program that stimulates CD8+ T cell activation and anti-tumor cytotoxicity. Inhibition of PI3Kγ re-polarized tumor associated macrophages and synergized with anti-PD-1 checkpoint inhibitor therapy to promote tumor clearance as well as lasting immunological anti-tumor memory in mouse models of cancer. In addition, we found that a PI3Kγ-directed, anti-inflammatory gene expression signature predicted poor survival in lung, breast, gastric and head and neck cancer patients. As a result of our findings, PI3Kγ inhibitors have entered solid tumor clinical trials at UCSD and elsewhere. In these proposed studies, we will evaluate the premise that PI3Kγ plays an essential role in tumor progression by regulating key signal transduction and transcription pathways that control myeloid cell trafficking and polarization. We will characterize the detailed molecular mechanisms by which myeloid cell PI3Kγ regulates tumor progression. We hypothesize that a precise understanding of the molecular events by which PI3Kγ regulates tumor progression will enable us to develop novel therapies for the treatment of these diseases. The specific aims of this proposal are: 1) To identify the molecular mechanisms by which PI3Kγ regulates macrophage/myeloid cell polarity and immune responses in vitro and in vivo; 2) To determine how PI3Kγ!regulates immune suppressive myeloid cell accumulation in tumors and develop strategies to inhibit their accumulation; and 3) To identify mechanisms by which PI3Kγ inhibition synergizes with cancer therapeutics to suppress tumor progression. !