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

Abstract

We attempted to determine whether the immune reactions elicited by aberrantly expressed testis antigens contribute to the beneficial responses to interferon (IFN)-α therapy and other therapies in patients with polycythemia vera (PV). We screened a human testis cDNA library using SEREX (serological analysis of tumor antigens by screening an expression cDNA library with sera from three patients with PV who had undergone IFN-α-induced or other therapeutics-induced remission). We identified two novel PV associated tumor antigens, PV65 (eIF-2α) and PV13 (protamine 2). These 2 antigens elicited IgG antibody reactions in a subset of PV patients but not in healthy donors, suggesting that they are authentic tumor antigens. Increased phosphorylation of PV65 in response to stimulation of IFN-α, and upregulation of PV13 in tumor cells might enhance their abilities in elicitation of immune reactions in patients. These findings provide new insights into the mechanism underlying the regulation of the self-antigen repertoire in eliciting anti-tumor immune reactions in patients with polycythemia vera, and suggest their potential as the targets 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.…”

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.…”

“…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. 44 These data suggest that IFN may act in PV by regulating self-antigen repertoires, which elicit antitumor immune reactions.…”

Increase in circulating CD4+CD25+Foxp3+ T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-α

“…[8][9][10][11][12][13][14] Even after discontinuation of therapy, some patients remain in molecular remission, with a JAK2 mutational burden Ͻ 1%, for years, which corresponds to a profound suppression of clonal myeloproliferation. 12 IFN-␣ is a very potent immune modulator [15][16][17][18] and might be able to "burst" immune surveillance and facilitate a stronger antitumor immune response against the JAK2 mutated clone and thus lead to eradication of tumor cells.…”