title: MHC class I loss is a frequent mechanism of immune escape in papillary thyroid cancer that is reversed by interferon and selumetinib treatment in vitro.
abstract: OBJECTIVE
  To evaluate MHC class I expression on papillary thyroid cancer (PTC) and analyze changes in MHC expression and associated immune activation with current and experimental treatments for thyroid cancer using in vitro PTC cell lines.
  
  
  METHODS
  MHC class I expression and assessment of tumor-infiltrating leukocyte populations were evaluated by immunohistochemistry. PTC cell lines were analyzed for HLA-ABC expression by flow cytometry following tyrosine kinase inhibitor, IFNα or IFNγ, or radiation treatment. Functional changes in antigenicity were assessed by coculture of allogeneic donor peripheral blood leukocytes (PBL) with pretreated or untreated PTC cell lines and measurement of T-cell activation and cytokine production.
  
  
  RESULTS
  Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations. Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. This phenotypic change was associated with increased T-cell activation (%CD25(+) of CD3(+)) and IL2 production by PBL cocultured with treated PTC cell lines. Additive effects were seen with combination selumetinib and IFN treatment.
  
  
  CONCLUSIONS
  MHC class I expression loss is frequent in human PTC specimens and represents a significant mechanism of immune escape. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC.
authors.affiliation: Division of Endocrinology and Diabetes, Keck Medical Center, University of Southern California, Los Angeles, California. Department of Pathology, Keck Medical Center, University of Southern California, Los Angeles, California. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Trevor E
authors.initials: TE
authors.lastname: Angell
authors.affiliation: Department of Pathology, Keck Medical Center, University of Southern California, Los Angeles, California. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Lechner
authors.affiliation: Department of Pathology, Keck Medical Center, University of Southern California, Los Angeles, California.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Jang
authors.affiliation: Division of Endocrinology and Diabetes, Keck Medical Center, University of Southern California, Los Angeles, California.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: LoPresti
authors.affiliation: Department of Pathology, Keck Medical Center, University of Southern California, Los Angeles, California. aepstein@usc.edu.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Epstein
mesh_terms: D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000494:pharmacology*; D015415:Biomarkers; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007372:Interferons / Q000494:pharmacology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape / Q000235:genetics* / Q000276:immunology*; D055815:Young Adult
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D015415:Biomarkers; D015395:Histocompatibility Antigens Class I; D047428:Protein Kinase Inhibitors; D007372:Interferons; D048493:Proto-Oncogene Proteins B-raf