Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kd/g

Ruth J. Davis, Ellen C. Moore, Paul E. Clavijo, Jay Friedman, Harrison Cash, Zhong Chen, Chris Silvin, Carter Van Waes, Clint T Allen

Research output: Contribution to journalArticle

Abstract

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 PI3Kδ and PI3Kgamma; 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 tumorinfiltrating T lymphocytes. Together, our results offer a preclinical proof of concept for the low-dose use of isoformspecific PI3Kδ/γ inhibitors to suppress MDSC to enhance responses to immune checkpoint blockade.

Original languageEnglish (US)
Pages (from-to)2607-2619
Number of pages13
JournalCancer Research
Volume77
Issue number10
DOIs
StatePublished - May 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Davis, R. J., Moore, E. C., Clavijo, P. E., Friedman, J., Cash, H., Chen, Z., Silvin, C., Van Waes, C., & Allen, C. T. (2017). Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kd/g. Cancer Research, 77(10), 2607-2619. https://doi.org/10.1158/0008-5472.CAN-16-2534