title: Epidermal growth factor receptor inhibition augments the expression of MHC class I and II genes.
abstract: OBJECTIVE
  Diverse immune-related effects occur with the use of epidermal growth factor receptor inhibitors (EGFRI). In addition to the cutaneous inflammation induced by EGFRIs, these agents have been associated with the exacerbation of autoimmune skin disease and contact hypersensitivity, antiviral effects, and fatal alveolar damage in the setting of lung transplantation. Because EGFR ligands can modulate MHC class I (MHCI) and II (MHCII) molecule expression, we hypothesized that some of the immune-related effects of EGFRIs are due to direct effects on the expression of MHCI and/or MHCII molecules.
  
  
  METHODS
  Primary human keratinocytes and a malignant keratinocyte cell line (A431) were treated with EGFRIs alone or prior to IFN-γ, a potent inducer of MHCI and MHCII molecule expression. CIITA, MHCI, and MHCII RNA expression was measured using quantitative real-time reverse transcriptase PCR, and cell surface MHCI and MHCII protein expression was measured using flow cytometry. Skin biopsies from patients were analyzed for MHCI and MHCII protein expression before and during therapy with an EGFRI using immunohistochemistry.
  
  
  RESULTS
  Both EGFR tyrosine kinase inhibitors and ligand-blocking antibodies (cetuximab) augmented the induction of MHCI and MHCII molecules by IFN-γ in primary and malignant human keratinocytes. Unexpectedly, the increase in MHCI protein expression did not require the presence of IFN-γ. Consistent with these in vitro findings, skin biopsies from cancer patients exhibited increased epidermal MHCI protein expression during therapy with an EGFRI as well as increases in MHCI and MHCII molecule RNA.
  
  
  CONCLUSIONS
  These studies suggest that EGFRIs may influence immune/inflammatory responses by directly modulating MHC expression. Clin Cancer Res; 17(13); 4400-13. ©2011 AACR.
authors.affiliation: Department of Dermatology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA. bppolla@emory.edu
authors.forename: Brian P
authors.initials: BP
authors.lastname: Pollack
authors.forename: Bishu
authors.initials: B
authors.lastname: Sapkota
authors.forename: Todd V
authors.initials: TV
authors.lastname: Cartee
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D002460:Cell Line; D045744:Cell Line, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D045325:HCT116 Cells; D006684:HLA-DR Antigens / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D006877:Hydroxamic Acids; D007155:Immunologic Factors; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; C509204:PD168393; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D015534:Trans-Activators; D007371:Interferon-gamma; C100342:marimastat; D066246:ErbB Receptors; D000068818:Cetuximab