@article{c7e738faf8384868babff2bc2c6cd792,
title = "A stealth antigen SPESP1, which is epigenetically silenced in tumors, is a suitable target for cancer immunotherapy",
abstract = "Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden “stealth” 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-aza-2′-deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re-expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re-expression in xenografts in BALB/c-nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T-cells with a SPESP1-derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1-specific helper T-cells were obtained; these cells produced interferon-γ against HLA-matched tumor cell lines treated with 5Aza. We also detected SPESP1 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.",
keywords = "DNA methylation, cancer immunoediting, cancer immunotherapy, stealth antigens, tumor immunoescape",
author = "Akemi Kosaka and Yuki Yajima and Mayumi Hatayama and Katsuya Ikuta and Takaaki Sasaki and Noriko Hirai and Syunsuke Yasuda and Marino Nagata and Ryusuke Hayashi and Shohei Harabuchi and Kenzo Ohara and Mizuho Ohara and Takumi Kumai and Kei Ishibashi and Yui Hirata-Nozaki and Toshihiro Nagato and Kensuke Oikawa and Yasuaki Harabuchi and Esteban Celis and Toshikatsu Okumura and Yoshinobu Ohsaki and Hiroya Kobayashi and Takayuki Ohkuri",
note = "Funding Information: Japan Society for the Promotion of Science (H Kobayashi 16K15244, and T Ohkuri 20K07367) and Japan Agency for Medical Research and Development AMED (A Kosaka JP16lm0103005). This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (H Kobayashi 16K15244 and T Ohkuri 20K07367) and Japan Agency for Medical Research and Development (AMED) (A Kosaka JP16lm0103005). The authors thank Mr. Hayakawa Toshiyuki and Ms. Hino Chihiro (at the Animal Laboratory for Medical Research, Center for Advanced Research and Education, Asahikawa Medical University) and Ms. Matsumoto Rie (at the Department of Pathology, Asahikawa Medical University) for devotedly maintaining the mice. Funding Information: This study was funded, in part, by Otsuka Pharmaceutical Co., Ltd. Funding Information: This work was supported by Grants‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (H Kobayashi 16K15244 and T Ohkuri 20K07367) and Japan Agency for Medical Research and Development (AMED) (A Kosaka JP16lm0103005). The authors thank Mr. Hayakawa Toshiyuki and Ms. Hino Chihiro (at the Animal Laboratory for Medical Research, Center for Advanced Research and Education, Asahikawa Medical University) and Ms. Matsumoto Rie (at the Department of Pathology, Asahikawa Medical University) for devotedly maintaining the mice. Publisher Copyright: {\textcopyright} 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.",
year = "2021",
month = jul,
doi = "10.1111/cas.14973",
language = "English (US)",
volume = "112",
pages = "2705--2713",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "7",
}