EGFR阻害薬はHERファミリー特異的T細胞の抗腫瘍効果を増強する 6

• 資料種別: 博士論文
• タイトル: EGFR阻害薬はHERファミリー特異的T細胞の抗腫瘍効果を増強する
• 巻次・部編番号: 109 6
• 著者・編者: 熊井, 琢美
• 出版年月日等: 2013-09
• 出版年（W3CDTF）: 2013-09
• 並列タイトル等: EGFR inhibitors augment antitumour helper T- cell responses of HER family-specific immunotherapy
• タイトル（掲載誌）: British Journal of Cancer
• 授与機関名: 旭川医科大学
• 授与年月日: 2014-03-25
• 授与年月日（W3CDTF）: 2014-03-25
• 報告番号: 甲第463号
• 学位: 博士(医学）
• 博論授与番号: 甲第463号
• 本文の言語コード: eng
• 件名標目: epidermal growth factor receptor (EGFR); head and neck squamous cell carcinoma (HNSCC); immunotherapy; tumour antigens; major histocompatibility complex class II; CD4 helper T lymphocytes
• 一般注記: BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related morbidity and mortality worldwide. Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive strategy alternative to conventional cancer treatments for HNSCC, but its efficacy remains controversial. T-cell-based immunotherapy has been proposed as a novel therapeutic approach to improve the clinical outcome for HNSCC. In this study, we report human epidermal receptor (HER) family epitopes that induced CD4 T-cell responses to HNSCC. The results provide support for a novel strategy to treat HNSCC by combining EGFR-targeted therapy with T-cell-based immunotherapy. METHODS: We evaluated the capacity of predicted CD4 T-cell peptide epitopes from EGFR to induce antitumour immune responses in vitro. In addition, EGFR inhibitors were evaluated for their ability to augment tumour MHC class II expression in HNSCC cell lines and subsequently increase T-cell recognition. RESULTS: Among several predicted peptide epitopes, EGFR875-889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope. The peptide-reactive T cells responded to autologous dendritic cells loaded with EGFR-expressing tumour cell lysates, indicating that these epitopes are naturally processed. In addition, the CD4 T cells were capable of directly recognising and killing HNSCC cells expressing EGFR and the appropriate HLA class II molecule. T cells reactive with the EGFR875-889 epitope could be detected in the blood of HNSCC patients. EGFR875-889-reactive CD4 T cells were also able to recognise several peptide analogues derived from homologous regions of EGFR family members, HER-2, HER-3 and c-MET. Finally, we examined the effects of EGFR tyrosine kinase inhibition or EGFR-blocking antibodies on CD4 T-cell tumour reactivity. Treatment of tumour cells with the EGFR inhibitors enhanced tumour recognition by EGFR875-889-reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells. CONCLUSION: We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR875-889 functions as a promiscuous helper T-cell epitope that can elicit effective antitumour T-cell responses against tumours expressing HER family members and c-MET. These observations should facilitate the translation of T-cell-based immunotherapy into the clinic for the treatment of HNSCC and provide a rational basis for EGFR inhibition, immune-targeted combination therapy.; identifier:PMID：24045666; 開始ページ : 2155; 終了ページ : 2166
• DOI: info:doi/10.1038/bjc.2013.577; https://doi.org/info:doi/10.1038/bjc.2013.577
• 国立国会図書館永続的識別子: info:ndljp/pid/11378574; https://dl.ndl.go.jp/pid/11378574
• コレクション（共通）: 障害者向け資料
• コレクション（障害者向け資料：レベル1）: テキストデータ
• コレクション（個別）: 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• 収集根拠: 博士論文（自動収集）
• 受理日（W3CDTF）: 2019-11-04T14:30:53+09:00
• 記録形式（IMT）: application/pdf
• オンライン閲覧公開範囲: 国立国会図書館内限定公開
• デジタル化資料送信: 図書館・個人送信対象外
• 遠隔複写可否（NDL）: 可
• 掲載誌（URI）: http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=20140325_K463
• 連携機関・データベース: 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp