title: Interferon Alpha Signalling and Its Relevance for the Upregulatory Effect of Transporter Proteins Associated with Antigen Processing (TAP) in Patients with Malignant Melanoma.
abstract: BACKGROUND
  Interferon alpha (IFNα) is routinely used in the clinical practice for adjuvant systemic melanoma therapy. Understanding the molecular mechanism of IFNα effects and prediction of response in the IFNα therapy regime allows initiation and continuation of IFNα treatment for responder and exclusion of non-responder to avoid therapy inefficacy and side-effects. The transporter protein associated with antigen processing-1 (TAP1) is part of the MHC class I peptide-loading complex, and important for antigen presentation in tumor and antigen presenting cells. In the context of personalized medicine, we address this potential biomarker TAP1 as a target of IFNα signalling.
  
  
  RESULTS
  We could show that IFNα upregulates TAP1 expression in peripheral blood mononuclear cells (PBMCs) of patients with malignant melanoma receiving adjuvant high-dose immunotherapy. IFNα also induced expression of TAP1 in mouse blood and tumor tissue and suppressed the formation of melanoma metastasis in an in vivo B16 tumor model. Besides its expression, TAP binding affinity and transport activity is induced by IFNα in human monocytic THP1 cells. Furthermore, our data revealed that IFNα clearly activates phosphorylation of STAT1 and STAT3 in THP1 and A375 melanoma cells. Inhibition of Janus kinases abrogates the IFNα-induced TAP1 expression. These results suggest that the JAK/STAT pathway is a crucial mediator for TAP1 expression elicited by IFNα treatment.
  
  
  CONCLUSIONS
  We suppose that silencing of TAP1 expression provides tumor cells with a mechanism to escape cytotoxic T-lymphocyte recognition. The observed benefit of IFNα treatment could be mediated by the shown dual effect of TAP1 upregulation in antigen presenting cells on the one hand, and of TAP1 upregulation in 'silent' metastatic melanoma cells on the other hand. In conclusion, this work contributes to a better understanding of the mode of action of IFNα which is essential to identify markers to predict, assess and monitor therapeutic response of IFNα treatment in the future.
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, Aachen, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Heise
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, Aachen, Germany.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Amann
authors.affiliation: IZKF, RWTH Aachen University, Aachen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Ensslen
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, Aachen, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Marquardt
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, Aachen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Czaja
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, Aachen, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Joussen
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, Aachen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Beer
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Abele
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Plewnia
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, Aachen, Germany.
authors.forename: Hans F
authors.initials: HF
authors.lastname: Merk
authors.affiliation: Medical Clinic and Policlinic II, Hepatology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Heike M
authors.initials: HM
authors.lastname: Hermanns
authors.affiliation: Department of Dermatology and Allergology, RWTH Aachen University, Aachen, Germany.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Baron
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D017951:Antigen Presentation; D006801:Humans; D007167:Immunotherapy; D016898:Interferon-alpha / Q000494:pharmacology / Q000502:physiology*; D053612:Janus Kinases; D007963:Leukocytes, Mononuclear; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C073119:TAP1 protein, human; D053612:Janus Kinases