title: Apigenin inhibits the inducible expression of programmed death ligand 1 by human and mouse mammary carcinoma cells.
abstract: Programmed death ligand 1 (PD-L1) is expressed by many cancer cell types, as well as by activated T cells and antigen-presenting cells. Constitutive and inducible PD-L1 expression contributes to immune evasion by breast cancer (BC) cells. We show here that the dietary phytochemical apigenin inhibited interferon (IFN)-γ-induced PD-L1 upregulation by triple-negative MDA-MB-468 BC cells, HER2(+) SK-BR-3 BC cells, and 4T1 mouse mammary carcinoma cells, as well as human mammary epithelial cells, but did not affect constitutive PD-L1 expression by triple-negative MDA-MB-231 BC cells. IFN-β-induced expression of PD-L1 by MDA-MB-468 cells was also inhibited by apigenin. In addition, luteolin, the major metabolite of apigenin, inhibited IFN-γ-induced PD-L1 expression by MDA-MB-468 cells. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 and 4T1 cells was associated with reduced phosphorylation of STAT1, which was early and transient at Tyr701 and sustained at Ser727. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 cells also increased proliferation and interleukin-2 synthesis by PD-1-expressing Jurkat T cells that were co-cultured with MDA-MB-468 cells. Apigenin therefore has the potential to increase the vulnerability of BC cells to T cell-mediated anti-tumor immune responses.
authors.affiliation: Department of Pathology, Dalhousie University, 5850 College St., PO Box 15000, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Melanie R Power
authors.initials: MRP
authors.lastname: Coombs
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, 5850 College St., PO Box 15000, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Harrison
authors.affiliation: Department of Pathology, Dalhousie University, 5850 College St., PO Box 15000, Halifax, Nova Scotia B3H 4R2, Canada; Department of Microbiology and Immunology, Dalhousie University, 5850 College St., PO Box 15000, Halifax, Nova Scotia B3H 4R2, Canada; Department of Surgery, Dalhousie University, 1278 Tower Rd., PO Box 15000, Halifax, Nova Scotia B3H 4R2, Canada. Electronic address: d.w.hoskin@dal.ca.
authors.forename: David W
authors.initials: DW
authors.lastname: Hoskin
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D047310:Apigenin / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D019169:Jurkat Cells; D047311:Luteolin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047310:Apigenin; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; D016899:Interferon-beta; D007371:Interferon-gamma; D047311:Luteolin; D018719:Erb-b2 Receptor Tyrosine Kinases; D050794:STAT1 Transcription Factor; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; C573415:IFNG protein, human; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C508053:ERBB2 protein, human
keywords: Breast cancer; Flavonoid; Immune evasion; PD-L1; Signal transduction