Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 10; pp. 2607 - 2619
• Main Authors: Davis, Ruth J, Moore, Ellen C, Clavijo, Paul E, Friedman, Jay, Cash, Harrison, Chen, Zhong, Silvin, Chris, Van Waes, Carter, Allen, Clint
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.05.2017
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents - pharmacology; B7-H1 Antigen - antagonists & inhibitors; Cancer; CD8 antigen; Cell culture; Cell Line, Tumor; Cell survival; Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Disease Models, Animal; Effector cells; Epitopes, T-Lymphocyte - immunology; Head & neck cancer; Head and neck; Immune checkpoint; Immunomodulation - drug effects; Immunosuppression; Inflammation; Inhibition; Inhibitors; Isoforms; Isoquinolines - pharmacology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Mice; Myeloid cells; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; PD-L1 protein; Protein Kinase Inhibitors - pharmacology; Purines - pharmacology; Suppressor cells; Survival Analysis; Tumor Microenvironment - immunology
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-2534

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. .