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. !
Tumor associated myeloid cells within the tumor microenvironment play critical roles in suppressing adaptive immunity and stimulating tumor cell proliferation, invasion and survival. Our studies have shown that phosphatidylinositol-4,5-bisphosphate 3-kinase gamma (PI3K?) and the pathways it controls drive cancer immune suppression; inhibitory targeting of this kinase stimulates anti-tumor immune responses that synergize with checkpoint inhibitors and chemotherapy. The overall goal of the proposed research is to delineate the mechanistic roles of PI3K? in the regulation of tumor inflammation, growth and metastasis and to use these discoveries to develop novel tumor therapeutic strategies.
| Foubert, Philippe; Kaneda, Megan M; Varner, Judith A (2017) PI3K? Activates Integrin ?4 and Promotes Immune Suppressive Myeloid Cell Polarization during Tumor Progression. Cancer Immunol Res 5:957-968 |
| Sato-Kaneko, Fumi; Yao, Shiyin; Ahmadi, Alast et al. (2017) Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer. JCI Insight 2: |
| Kaneda, Megan M; Messer, Karen S; Ralainirina, Natacha et al. (2016) PI3K? is a molecular switch that controls immune suppression. Nature 539:437-442 |
| Kaneda, Megan M; Cappello, Paola; Nguyen, Abraham V et al. (2016) Macrophage PI3K? Drives Pancreatic Ductal Adenocarcinoma Progression. Cancer Discov 6:870-85 |
| Gunderson, Andrew J; Kaneda, Megan M; Tsujikawa, Takahiro et al. (2016) Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer. Cancer Discov 6:270-85 |
| Young, Shanique A; McCabe, Katelyn E; Bartakova, Alena et al. (2015) Integrin ?4 Enhances Metastasis and May Be Associated with Poor Prognosis in MYCN-low Neuroblastoma. PLoS One 10:e0120815 |
| Garmy-Susini, Barbara; Avraamides, Christie J; Desgrosellier, Jay S et al. (2013) PI3K? activates integrin ?4?1 to establish a metastatic niche in lymph nodes. Proc Natl Acad Sci U S A 110:9042-7 |
| Schmid, Michael C; Franco, Irene; Kang, Sang Won et al. (2013) PI3-kinase ? promotes Rap1a-mediated activation of myeloid cell integrin ?4?1, leading to tumor inflammation and growth. PLoS One 8:e60226 |
| Schmid, Michael C; Varner, Judith A (2012) Myeloid cells in tumor inflammation. Vasc Cell 4:14 |
| Kato, Hisashi; Liao, Zhongji; Mitsios, John V et al. (2012) The primacy of ?1 integrin activation in the metastatic cascade. PLoS One 7:e46576 |
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