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 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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Davis RJ,Moore EC,Clavijo PE,Friedman J,Cash H,Chen Z,Silvin C,Van Waes C,Allen Cdoi
10.1158/0008-5472.CAN-16-2534subject
Has Abstractpub_date
2017-05-15 00:00:00pages
2607-2619issue
10eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-16-2534journal_volume
77pub_type
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