Effects of novel isoform-selective phosphoinositide 3-kinase inhibitors on natural killer cell function. PLoS One 2014;9(6):e99486
Date
06/11/2014Pubmed ID
24915189Pubmed Central ID
PMC4051752DOI
10.1371/journal.pone.0099486Scopus ID
2-s2.0-84902578296 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
Phosphoinositide 3-kinases (PI3Ks) are promising targets for therapeutic development in cancer. The class I PI3K isoform p110α has received considerable attention in oncology because the gene encoding p110α (PIK3CA) is frequently mutated in human cancer. However, little is known about the function of p110α in lymphocyte populations that modulate tumorigenesis. We used recently developed investigational inhibitors to compare the function of p110α and other isoforms in natural killer (NK) cells, a key cell type for immunosurveillance and tumor immunotherapy. Inhibitors of all class I isoforms (pan-PI3K) significantly impaired NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity against tumor cells, whereas p110α-selective inhibitors had no effect. In NK cells stimulated through NKG2D, p110α inhibition modestly reduced PI3K signaling output as measured by AKT phosphorylation. Production of IFN-γ and NK cell-derived chemokines was blocked by a pan-PI3K inhibitor and partially reduced by a p110δinhibitor, with lesser effects of p110α inhibitors. Oral administration of mice with MLN1117, a p110α inhibitor in oncology clinical trials, had negligible effects on NK subset maturation or terminal subset commitment. Collectively, these results support the targeting of PIK3CA mutant tumors with selective p110α inhibitors to preserve NK cell function.
Author List
Yea SS, So L, Mallya S, Lee J, Rajasekaran K, Malarkannan S, Fruman DAAuthor
Subramaniam Malarkannan PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibody-Dependent Cell Cytotoxicity
Cell Differentiation
Cell Survival
Chemokines
Cytotoxicity, Immunologic
Female
Humans
Interferon-gamma
Isoenzymes
Killer Cells, Natural
Mice, Inbred C57BL
NK Cell Lectin-Like Receptor Subfamily K
Phosphatidylinositol 3-Kinases
Phosphorylation
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
