Role of PI3Kinase in Tumor Progression and Metastasis

实体瘤的特征在于丰富的促肿瘤炎性浸润，其包含 主要是免疫抑制性巨噬细胞、单核细胞和粒细胞。这些免疫抑制细胞 阻止肿瘤微环境中的T细胞募集和/或活化并刺激肿瘤血管生成 和转移。由于2015年美国将诊断出大约170万例新的癌症病例， 2016年，仅2016年就有60万患者死于癌症，因此迫切需要推进研究 免疫抑制性骨髓细胞促进肿瘤进展的机制， 开发可以靶向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应答之间的关键开关， 在炎症和癌症期间抑制。我们发现PI 3 K γ促进骨髓细胞的募集， 肿瘤免疫抑制极化。PI 3 K γ通过mTor和Akt信号传导诱导免疫应答。 抑制T细胞活化的抑制性转录程序。相反，选择性失活 巨噬细胞PI 3 K γ刺激NFκB和TBK 1，从而促进免疫刺激性转录程序 刺激CD 8 + T细胞活化和抗肿瘤细胞毒性。抑制PI 3 K γ再极化肿瘤 相关的巨噬细胞，并与抗PD-1检查点抑制剂疗法协同作用，以促进肿瘤 清除以及持久的免疫抗肿瘤记忆。另外我们 发现PI 3 K γ导向的抗炎基因表达特征预测肺部存活率低， 乳腺癌、胃癌和头颈癌患者。由于我们的发现，PI 3 K γ抑制剂已经进入了 在加州大学圣地亚哥分校和其他地方进行的实体瘤临床试验。 在这些拟议的研究中，我们将评估PI 3 K γ在肿瘤中起重要作用的前提 通过调节控制骨髓细胞的关键信号转导和转录途径来进展 贩运和两极分化。我们将详细描述髓系细胞 PI 3 K γ调节肿瘤进展。我们假设，通过对分子事件的精确理解， PI 3 K γ调节肿瘤进展将使我们能够开发新的治疗方法来治疗这些疾病。 疾病本研究的具体目的是：1）明确PI 3 K γ在细胞内的表达及其与细胞凋亡的关系， 在体外和体内调节巨噬细胞/骨髓细胞极性和免疫反应; 2）为了确定如何 PI3Kγ！调节肿瘤中的免疫抑制性骨髓细胞积聚，并开发抑制其 3）确定PI 3 K γ抑制与癌症治疗协同作用的机制， 抑制肿瘤进展。 !

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. !