Journal
CANCER RESEARCH
Volume 77, Issue 10, Pages 2607-2619Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-2534
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Funding
- NIH, NIDCD [ZIA-DC000087]
- American Academy of Otolaryngology/American Head and Neck Society Duane Sewell Young Investigators Combined Award
- NIH Medical Research Scholars Program
- NIH
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Checkpoint inhibitors are relatively inefficacious in head and neck cancers, despite an abundance of genetic alterations and a T-cell-inflamed phenotype. One significant barrier to efficacy may be the recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment. Here we demonstrate functional inhibition of MDSC with IPI-145, an inhibitor of PI3K delta and PI3K gamma isoforms, which enhances responses to PD-L1 blockade. Combination therapy induced CD8(+) T lymphocyte-dependent primary tumor growth delay and prolonged survival only in T-cell-inflamed tumor models of head and neck cancers. However, higher doses of IPI-145 reversed the observed enhancement of anti-PD-L1 efficacy due to off-target suppression of the activity of tumor-infiltrating T lymphocytes. Together, our results offer a preclinical proof of concept for the low-dose use of isoform-specific PI3K delta/gamma inhibitors to suppress MDSC to enhance responses to immune checkpoint blockade. (C) 2017 AACR.
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