Role of PI3Kinase in Tumor Progression and Metastasis

University Of California, San Diego, La Jolla CA

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Abstract

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 ? controls a critical switch between immune stimulation and immune suppression during inflammation and cancer. We found that PI3K? promotes both myeloid cell recruitment and immune suppressive polarization in tumors. PI3K? signals through mTor and Akt to induce an immune suppressive transcriptional program that inhibits T cell activation. In contrast, selective inactivation of macrophage PI3K? stimulates NF?B and TBK1, thus promoting an immunostimulatory transcriptional program that stimulates CD8+ T cell activation and anti-tumor cytotoxicity. Inhibition of PI3K? 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 PI3K?-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, PI3K? inhibitors have entered solid tumor clinical trials at UCSD and elsewhere. In these proposed studies, we will evaluate the premise that PI3K? 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 PI3K? regulates tumor progression. We hypothesize that a precise understanding of the molecular events by which PI3K? 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 PI3K? regulates macrophage/myeloid cell polarity and immune responses in vitro and in vivo; 2) To determine how PI3K?!regulates immune suppressive myeloid cell accumulation in tumors and develop strategies to inhibit their accumulation; and 3) To identify mechanisms by which PI3K? inhibition synergizes with cancer therapeutics to suppress tumor progression. !