title: Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ.
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.
authors.affiliation: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Moore
authors.affiliation: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Clavijo
authors.affiliation: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland.
authors.forename: Jay
authors.initials: J
authors.lastname: Friedman
authors.affiliation: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland.
authors.forename: Harrison
authors.initials: H
authors.lastname: Cash
authors.affiliation: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland.
authors.forename: Chris
authors.initials: C
authors.lastname: Silvin
authors.affiliation: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland.
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
authors.affiliation: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland. clint.allen@nih.gov.|Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Clint
authors.initials: C
authors.lastname: Allen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D056747:Immunomodulation / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D016019:Survival Analysis; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D018984:Epitopes, T-Lymphocyte; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011687:Purines; C586691:duvelisib; D058534:Class I Phosphatidylinositol 3-Kinases