Interruption of MDM2 signaling augments MDM2-targeted T cell-based antitumor immunotherapy through antigen-presenting machinery

Michihisa Kono, Takumi Kumai, Ryusuke Hayashi, Hidekiyo Yamaki, Hiroki Komatsuda, Risa Wakisaka, Toshihiro Nagato, Takayuki Ohkuri, Akemi Kosaka, Kenzo Ohara, Kan Kishibe, Miki Takahara, Akihiro Katada, Tatsuya Hayashi, Esteban Celis, Hiroya Kobayashi, Yasuaki Harabuchi

Research output: Contribution to journalArticlepeer-review

Abstract

Identification of immunogenic tumor antigens, their corresponding T cell epitopes and the selection of effective adjuvants are prerequisites for developing effective cancer immunotherapies such as therapeutic vaccines. Murine double minute 2 (MDM2) is an E3 ubiquitin-protein ligase that negatively regulates tumor suppressor p53. Because MDM2 overexpression serves as a poor prognosis factor in various types of tumors, it would be beneficial to develop MDM2-targeted cancer vaccines. In this report, we identified an MDM2-derived peptide epitope (MDM232-46) that elicited antigen-specific and tumor-reactive CD4+ T cell responses. These CD4+ T cells directly killed tumor cells via granzyme B. MDM2 is expressed in head and neck cancer patients with poor prognosis, and the T cells that recognize this MDM2 peptide were present in these patients. Notably, Nutlin-3 (MDM2-p53 blocker), inhibited tumor cell proliferation, was shown to augment antitumor T cell responses by increasing MDM2 expression, HLA-class I and HLA-DR through class II transactivator (CIITA). These results suggest that the use of this MDM2 peptide as a therapeutic vaccine combined with MDM2 inhibitors could represent an effective immunologic strategy to treat cancer.

Original languageEnglish (US)
JournalCancer Immunology, Immunotherapy
DOIs
StateAccepted/In press - 2021

Keywords

  • Head and neck squamous cell carcinoma
  • Immunotherapy
  • MDM2
  • MDM2 inhibitor
  • Peptide vaccine
  • Tumor-associated antigen

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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