A Novel Mechanism in Generation of Self-Antigen Repertoire - An Unconventional Antigen Translated by a Novel Internal Ribosome Entry Site Elicits Anti-Tumor Humoral Immune Responses

Self-tumor antigens that elicit anti-tumor immune/autoimmune responses in responses to interferon-a (IFN-a) stimulation remain poorly defined. We screened a human testis cDNA library with sera from three polycythemia vera (PV) patients who responded to IFN-a and identified a novel antigen, MPD6. MPD6 belongs to the group of cryptic antigens without conventional genomic structure and is encoded by a cryptic open reading frame located in the 3′untranslated region (3′UTR) of myotrophin mRNA. MPD6 elicits IgG antibody responses in a subset of PV patients, as well as patients with chronic myelogenous leukemia and prostate cancer, suggesting that it is broadly immunogenic. The expression of myotrophin-MPD6 transcripts in tumor cells was upregulated in some tumor cells, but only slightly increased in K562 cells in response to IFN-a 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 upregulated in response to IFN-a stimulation. These findings demonstrate for the first time that a novel IRES-mediated mechanism is responsible for the translation of unconventional self-antigen MPD6 in responsive to IFN-a stimulation. The eliciting anti-tumor immune response against unconventional antigen MPD6 in patients with myeloproliferative diseases suggests MPD6 as a potential target of novel immunotherapy. Our results also suggest that the enhancement of IRES-mediated translation of unconventional self-antigen(s) by IFN-a is a novel mechanism of IFN-a enhanced anti-tumor immune/autoimmune responses.