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. !

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA167426-07
Application #
9688929
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Isaacs, Jennifer S
Project Start
2012-04-01
Project End
2023-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Kaneda, Megan M; Messer, Karen S; Ralainirina, Natacha et al. (2016) PI3K? is a molecular switch that controls immune suppression. Nature 539:437-442
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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
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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
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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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