# Role of PI3Kinase in Tumor Progression and Metastasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $295,139

## 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 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.
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## Key facts

- **NIH application ID:** 10116294
- **Project number:** 5R01CA167426-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Judith A VARNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $295,139
- **Award type:** 5
- **Project period:** 2012-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116294

## Citation

> US National Institutes of Health, RePORTER application 10116294, Role of PI3Kinase in Tumor Progression and Metastasis (5R01CA167426-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10116294. Licensed CC0.

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