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- Title
Interruption of MDM2 signaling augments MDM2-targeted T cell-based antitumor immunotherapy through antigen-presenting machinery.
- Authors
Kono, Michihisa; Kumai, Takumi; Hayashi, Ryusuke; Yamaki, Hidekiyo; Komatsuda, Hiroki; Wakisaka, Risa; Nagato, Toshihiro; Ohkuri, Takayuki; Kosaka, Akemi; Ohara, Kenzo; Kishibe, Kan; Takahara, Miki; Katada, Akihiro; Hayashi, Tatsuya; Celis, Esteban; Kobayashi, Hiroya; Harabuchi, Yasuaki
- 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.
- Subjects
T cell receptors; ANTIGENS; HEAD &; neck cancer; IMMUNOTHERAPY; INHIBITION of cellular proliferation; UBIQUITIN ligases; TUMOR antigens
- Publication
Cancer Immunology, Immunotherapy, 2021, Vol 70, Issue 12, p3421
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-021-02940-5