A stealth antigen SPESP1, which is epigenetically silenced in tumors, is a suitable target for cancer immunotherapy

Akemi Kosaka, Yuki Yajima, Mayumi Hatayama, Katsuya Ikuta, Takaaki Sasaki, Noriko Hirai, Syunsuke Yasuda, Marino Nagata, Ryusuke Hayashi, Shohei Harabuchi, Kenzo Ohara, Mizuho Ohara, Takumi Kumai, Kei Ishibashi, Yui Hirata-Nozaki, Toshihiro Nagato, Kensuke Oikawa, Yasuaki Harabuchi, Esteban Celis, Toshikatsu OkumuraYoshinobu Ohsaki, Hiroya Kobayashi, Takayuki Ohkuri

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2705-2713
Number of pages9
JournalCancer Science
Volume112
Issue number7
DOIs
StatePublished - Jul 2021

Keywords

  • DNA methylation
  • cancer immunoediting
  • cancer immunotherapy
  • stealth antigens
  • tumor immunoescape

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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