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We hypothesized that these epigenetically hidden \u201cstealth\u201d antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5\u2010aza\u20102\u2032\u2010deoxycytidine (5Aza) and its prodrug guadecitabine for 3\u00a0d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re\u2010expressed in cell lines including solid tumors and leukemias treated with 5Aza, although <jats:italic>SPESP1<\/jats:italic> was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that <jats:italic>SPESP1<\/jats:italic> was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re\u2010expression in xenografts in BALB\/c\u2010nu\/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4<jats:sup>+<\/jats:sup> T\u2010cells with a SPESP1\u2010derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1\u2010specific helper T\u2010cells were obtained; these cells produced interferon\u2010\u03b3 against HLA\u2010matched tumor cell lines treated with 5Aza. We also detected <jats:italic>SPESP1<\/jats:italic> expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy.<\/jats:p>","DOI":"10.1111\/cas.14973","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T16:38:38Z","timestamp":1621442318000},"page":"2705-2713","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A stealth antigen SPESP1, which is epigenetically silenced in tumors, is a suitable target for cancer immunotherapy"],"prefix":"10.1111","volume":"112","author":[{"given":"Akemi","family":"Kosaka","sequence":"first","affiliation":[{"name":"Department of Pathology Asahikawa Medical University Asahikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Yajima","sequence":"additional","affiliation":[{"name":"Department of Pathology Asahikawa 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