title: Effects of novel isoform-selective phosphoinositide 3-kinase inhibitors on natural killer cell function.
abstract: 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.
authors.affiliation: Department of Molecular Biology & Biochemistry, and Institute for Immunology, University of California Irvine, Irvine, California, United States of America; Department of Biochemistry, College of Medicine, Inje University, Busan, Korea.
authors.forename: Sung Su
authors.initials: SS
authors.lastname: Yea
authors.affiliation: Department of Molecular Biology & Biochemistry, and Institute for Immunology, University of California Irvine, Irvine, California, United States of America.
authors.forename: Lomon
authors.initials: L
authors.lastname: So
authors.affiliation: Department of Molecular Biology & Biochemistry, and Institute for Immunology, University of California Irvine, Irvine, California, United States of America.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Mallya
authors.affiliation: Department of Molecular Biology & Biochemistry, and Institute for Immunology, University of California Irvine, Irvine, California, United States of America.
authors.forename: Jongdae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Milwaukee, Wisconsin, United States of America.
authors.forename: Kamalakannan
authors.initials: K
authors.lastname: Rajasekaran
authors.affiliation: Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Milwaukee, Wisconsin, United States of America.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Malarkannan
authors.affiliation: Department of Molecular Biology & Biochemistry, and Institute for Immunology, University of California Irvine, Irvine, California, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Fruman
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018925:Chemokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D018925:Chemokines; D007371:Interferon-gamma; D007527:Isoenzymes; D055655:NK Cell Lectin-Like Receptor Subfamily K; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C527085:KLRK1 protein, human