An unconventional antigen translated by a novel internal ribosome entry site elicits antitumor humoral immune reactions.
Self-tumor Ags that elicit antitumor immune responses in responses to IFN-alpha stimulation remain poorly defined. We screened a human testis cDNA library with sera from three polycythemia vera patients who responded to IFN-alpha and identified a novel Ag, MPD6. MPD6 belongs to the group of cryptic Ags without conventional genomic structure and is encoded by a cryptic open reading frame located in the 3'-untranslated region of myotrophin mRNA. MPD6 elicits IgG Ab responses in a subset of polycythemia vera patients, as well as patients with chronic myelogenous leukemia and prostate cancer, suggesting that it is broadly immunogenic. The expression of myotrophin-MPD6 transcripts was up-regulated in some tumor cells, but only slightly increased in K562 cells in response to IFN-alpha treatment. By using bicistronic reporter constructs, we showed that the translation of MPD6 was mediated by a novel internal ribosome entry site (IRES) upstream of the MPD6 reading frame. Furthermore, the MPD6-IRES-mediated translation, but not myotrophin-MPD6 transcription, was significantly up-regulated in response to IFN-alpha stimulation. These findings demonstrate that a novel IRES-mediated mechanism may be responsible for the translation of unconventional self-Ag MPD6 in responsive to IFN-alpha stimulation. The eliciting antitumor immune response against unconventional Ag MPD6 in patients with myeloproliferative diseases suggests MPD6 as a potential target of novel immunotherapy.
Xiong
Zeyu
Z
Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA.
Liu
Enli
E
Yan
Yan
Y
Silver
Richard T
RT
Yang
Fan
F
Chen
Irene H
IH
Chen
Yangyang
Y
Verstovsek
Srdan
S
Wang
Hong
H
Prchal
Josef
J
Yang
Xiao-Feng
XF
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D015152:Blotting, Northern; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D015723:Gene Library; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D011087:Polycythemia Vera / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology; D014176:Protein Biosynthesis; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012270:Ribosomes / Q000737:chemistry / Q000235:genetics* / Q000648:ultrastructure; D013737:Testis / Q000502:physiology
D000951:Antigens, Neoplasm; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C065700:myotrophin; D007371:Interferon-gamma