Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kδ/γ

RJ Davis, EC Moore, PE Clavijo, J Friedman, H Cash… - Cancer research, 2017 - AACR
RJ Davis, EC Moore, PE Clavijo, J Friedman, H Cash, Z Chen, C Silvin, C Van Waes…
Cancer research, 2017AACR
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 …
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.
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