title: PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses.
abstract: Purpose:Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,β in tumor growth and PI3Kγ,δ in immune cell function, we sought to determine whether PI3K inhibition altered antitumor immunity.Experimental Design:The effect of PI3K inhibition on tumor growth, metastasis, and antitumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic orPI3Kγ-null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor-infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30 mg/kg, every day) or vehicle-treated mice andPI3KγnullversusPI3KγWTmice. On the basis of the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30 mg/kg, every day) and anti-PD1 (100 μg, twice weekly) was evaluated in PyMT tumor-bearing mice.Results:Our findings show that PI3K activity facilitates tumor growth and surprisingly restrains tumor immune surveillance. These activities could be partially suppressed by BKM120 or by genetic deletion ofPI3Kγin the host. The antitumor effect ofPI3Kγloss in host, but not tumor, was partially reversed by CD8+T-cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared with either agent alone.Conclusions:PI3K inhibition slows tumor growth, enhances antitumor immunity, and heightens susceptibility to immune checkpoint inhibitors. We propose that combining PI3K inhibition with anti-PD1 may be a viable therapeutic approach for triple-negative breast cancer.Clin Cancer Res; 23(13); 3371-84. ©2016 AACR.
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Sai
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Philip
authors.initials: P
authors.lastname: Owens
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Novitskiy
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Oriana E
authors.initials: OE
authors.lastname: Hawkins
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Vilgelm
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jinming
authors.initials: J
authors.lastname: Yang
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Tammy
authors.initials: T
authors.lastname: Sobolik
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lavender
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Johnson
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Colt
authors.initials: C
authors.lastname: McClain
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Ayers
authors.affiliation: Department of Surgical Oncology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kelley
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Melinda
authors.initials: M
authors.lastname: Sanders
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Mark
authors.initials: M
authors.lastname: Boothby
authors.affiliation: Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee. ann.richmond@vanderbilt.edu.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics*; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage; D009362:Neoplasm Metastasis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120; C491383:Pdcd1 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse