A synthetic peptide homologous to functional domain of human IL-10 down-regulates expression of MHC class I and Transporter associated with Antigen Processing 1/2 in human melanoma cells.
Tumor cells treated with IL-10 were shown to have decreased, but peptide-inducible expression of MHC class I, decreased sensitivity to MHC class I-restricted CTL, and increased NK sensitivity. These findings could be explained, at least partially, by a down-regulation of TAP1/TAP2 expression. In this study, IT9302, a nanomeric peptide (AYMTMKIRN), homologous to the C-terminal of the human IL-10 sequence, was demonstrated to mimic these previously described IL-10 effects on MHC class I-related molecules and functions. We observed a dose-dependent down-regulation of MHC class I at the cell surface of melanoma cells after 24-h treatment with IT9302. The IL-10 homologue peptide also caused a dose-dependent inhibition of the IFN-gamma-mediated surface induction of MHC class I in a melanoma cell line. We demonstrated, using Western blot and flow cytometry, that IT9302 inhibits the expression of TAP1 and TAP2 proteins, but not MHC class I H chain or low molecular protein molecules. Finally, peptide-treated melanoma cells were shown to be more sensitive to lysis by NK cells in a dose-dependent way. Taken together, these results demonstrate that a small synthetic peptide derived from IL-10 can mimic the Ag presentation-related effects mediated by this cytokine in human melanomas and increase tumor sensitivity to NK cells, which can be relevant in the designing of future strategies for cancer immune therapy.
Kurte
Mónica
M
Disciplinary Program of Immunology, Faculty of Medicine, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
López
Mercedes
M
Aguirre
Adam
A
Escobar
Alejandro
A
Aguillón
Juan Carlos
JC
Charo
Jehad
J
Larsen
Christian G
CG
Kiessling
Rolf
R
Salazar-Onfray
Flavio
F
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D004305:Dose-Response Relationship, Drug; D005134:Eye Neoplasms / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016753:Interleukin-10 / Q000819:agonists* / Q000737:chemistry; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D009363:Neoplasm Proteins; D009842:Oligopeptides; D011994:Recombinant Proteins; C073119:TAP1 protein, human; D016753:Interleukin-10; C071313:LMP-2 protein; C071692:TAP2 protein, human; C114519:alanyl-tyrosyl-methionyl-threonyl-methionyl-lysyl-isoleucyl-arginyl-asparagine; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases