An Unconventional Antigen Translated by a Novel Internal Ribosome Entry Site Elicits Antitumor Humoral Immune Reactions

Abstract

Self-tumor Ags that elicit antitumor immune responses in responses to IFN-α stimulation remain poorly defined. We screened a human testis cDNA library with sera from three polycythemia vera patients who responded to IFN-α 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-α 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-α 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-α stimulation. The eliciting antitumor immune response against unconventional Ag MPD6 in patients with myeloproliferative diseases suggests MPD6 as a potential target of novel immunotherapy.

Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera

“…45,46 In this regard, the recently identified PV-associated tumor antigens may represent targets for immune effectors. 47,48 The time interval between hematologic and MRs observed in the present study could suggest that direct cytotoxic and antiproliferative properties of IFN were responsible for the rapid hematologic response (within 3 months in ϳ 90% of the patients), whereas immune-mediated mechanisms could be involved in MR, achieved later.…”

Novel tumor antigens elicit anti-tumor humoral immune reactions in a subset of patients with polycythemia vera

“…To our knowledge, this is a part of the first such a study in BCR-ABL negative MPD [1,6]. The analyses showed that these novel tumor antigens are not identical to any hematologic malignancy antigens identified previously with SEREX [17] or other approaches [22,42].…”

“…Despite significant progress, the self-antigen targets that may mediate immune reactions contributing to beneficial responses to therapies in patients with myeloproliferative diseases (MPD) remained poorly defined before our recent report in characterization of a new unconventional tumor antigen MPD6 [6]. Recent reports showed that mRNA of polycythemia rubra vera-1 (PRV-1) is overexpressed in mature peripheral blood granulocytes from patients with PV [38,39].…”

“…Cytogenetic response to IFN-α therapy in CML [4], is often associated with therapy-related autoimmunity [5], suggesting that anti-self antigen immune reactions may play an important role in controlling tumors. However, the potential self-antigens eliciting anti-PV immune reactions remained largely unknown until our recent report in characterization of a new unconventional tumor antigen MPD6 [6].…”

The renaissance of interferon therapy for the treatment of myeloid malignancies

“…Expression of novel antigens by PV cells that are capable of eliciting a potent humoral immune response has been associated with the achievement of molecular remissions. 42,43 IFN␣ therapy has been reported to up-regulate a putative tumor antigen termed MPD6, which is encoded by a cryptic open reading frame located in the 3Ј-untranslated region of myotrophin mRNA by a novel internal ribosome entry site upstream of the MPD6 reading frame. 43 Furthermore, type 1 IFNs also enhance antibody responses to soluble antigens and promote immunoglobulin class switching.…”