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Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3K{delta}/{gamma}

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 PI3Kγ 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 PI3Kδ/γ inhibitors to suppress MDSC to enhance responses to immune checkpoint blockade. Cancer Res; 77(10); 2607–19. ©2017 AACR .

Autoren:   Ruth J. Davis; Ellen C. Moore; Paul E. Clavijo; Jay Friedman; Harrison Cash; Zhong Chen; Chris Silvin; Carter Van Waes; Clint Allen
Journal:   Cancer Research
Band:   77
Ausgabe:   10
Jahrgang:   2017
Seiten:   2607
DOI:   10.1158/0008-5472.CAN-16-2534
Erscheinungsdatum:   15.05.2017
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