Investigation of neo-self antigens derived from proteins with post-translational modification

• Project/Area Number: 18K19485
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Kiyotani Kazuma 公益財団法人がん研究会, がんプレシジョン医療研究センター 免疫ゲノム医療開発プロジェクト, 主任研究員 (30433642)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 翻訳後修飾 / ネオセルフ抗原 / T細胞受容体 / ネオアンチゲン / LC-MS/MS

Outline of Final Research Achievements

In this study, we investigated whether neo-self peptides derived from mutilated proteins encoded by oncogenes. We generated all possible peptides with methylated amino acid using bioinformatic approach and predicted their binding affinities to HLA class I molecules. Through the analysis, we obtained two possible candidates of methylated proteins which can be presented on HLA molecules. From HLA-matched healthy donor’s blood sample, we successfully induced methylated peptide-specific T cells for one of them. We also identified the TCRalpha/beta sequences of the T cells, and generated TCR-engineered T cells.

Academic Significance and Societal Importance of the Research Achievements

本研究では、翻訳後修飾（特にメチル化）を受けたタンパク質由来の抗原がT細胞の標的となりうるかを検証した。これまでに翻訳後修飾を受けたペプチドがHLA上に提示されていることは報告されていた。本研究では、実際に初めて翻訳後修飾を受けたペプチドを特異的に認識するT細胞の同定に成功した。本研究の成果は、学術的にも、また新たながん免疫療法の標的としても大変重要な成果である。

Research Products

• [Journal Article] Cooperation of genes in HPV16 E6/E7-dependent cervicovaginal carcinogenesis trackable by endoscopy and independent of exogenous estrogens or carcinogens (2020)
  • Author(s): Paula Bottinger, Kiyotani Kazuma, et al.
  • Journal Title: Carcinogenesis Volume: . Issue: 11 Pages: 1605-1615
  • DOI: 10.1093/carcin/bgaa027
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of TCR Diversity on the Development of Transplanted or Chemically Induced Tumors (2019)
  • Author(s): Schreiber K, Karrison G, Wolf SP, Kiyotani K, Steiner M, Littmann ER, Pamer EG, Kammertoens T, Schreiber H, Leisegang M.
  • Journal Title: Cancer Immunology Research Volume: 8 Issue: 2 Pages: 192-202
  • DOI: 10.1158/2326-6066.cir-19-0567
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Diagnostic utility of STAT6YE361 expression in classical Hodgkin lymphoma and related entities (2019)
  • Author(s): Slambrouck CV, Huh J, Suh C, Song JY, Menon MP, Sohani AR, Duffield AS, Goldberg RC, Dama P, Kiyotani K, Godfrey J, Fitzpatrick C, Kline J, Smith SM, Jaffe ES, Hartmann S, Venkataraman G.
  • Journal Title: Modern Pathology Volume: 33 Issue: 5 Pages: 834-845
  • DOI: 10.1038/s41379-019-0428-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Tamoxifen Metabolism and Breast Cancer Recurrence: A Question Unanswered by CYPTAM (2019)
  • Author(s): Goetz MP, Suman VJ, Nakamura Y, Kiyotani K, Jordan VC, Ingle JN.
  • Journal Title: Journal of Clinical Oncology Volume: 37 Issue: 22 Pages: 1982-1983
  • DOI: 10.1200/jco.19.00504
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer (2019)
  • Author(s): Gong Bo, Kiyotani Kazuma, Sakata Seiji, Nagano Seiji, Kumehara Shun, Baba Satoko, Besse Benjamin, Yanagitani Noriko, Friboulet Luc, Nishio Makoto, Takeuchi Kengo, Kawamoto Hiroshi, Fujita Naoya, Katayama Ryohei
  • Journal Title: The Journal of Experimental Medicine Volume: 216 Issue: 4 Pages: 982-1000
  • DOI: 10.1084/jem.20180870
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TCR sequencing analysis of cancer tissues and tumor draining lymph nodes in colorectal cancer patients. (2019)
  • Author(s): Tatsuo Matsuda, Eisaku Miyauchi, Yu-Wen Hsu, Satoshi Nagayama, Kazuma Kiyotani, Makda Zewde, Jae-Hyun Park, Taigo Kato, Makiko Harada, Shimpei Matsui, Masashi Ueno, Kazumasa Fukuda, Nobuaki Suzuki, Shoichi Hazama, Hiroaki Nagano, Hiroya Takeuchi, Wickii T. Vigneswaran, Yuko Kitagawa, Yusuke Nakamura
  • Journal Title: OncoImmunology Volume: 8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of neoantigen-specific T cells and their targets: implications for immunotherapy of head and neck squamous cell carcinoma (2019)
  • Author(s): Ren Lili、Leisegang Matthias、Deng Boya、Matsuda Tatsuo、Kiyotani Kazuma、Kato Taigo、Harada Makiko、Park Jae-Hyun、Saloura Vassiliki、Seiwert Tanguy、Vokes Everett、Agrawal Nishant、Nakamura Yusuke
  • Journal Title: OncoImmunology Volume: 8 Issue: 4 Pages: e1568813-e1568813
  • DOI: 10.1080/2162402x.2019.1568813
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without epidermal growth factor receptor mutations (2019)
  • Author(s): Miyauchi Eisaku、Matsuda Tatsuo、Kiyotani Kazuma、Low Siew-Kee、Hsu Yu-Wen、Tsukita Yoko、Ichinose Masakazu、Sakurada Akira、Okada Yoshinori、Saito Ryoko、Nakamura Yusuke
  • Journal Title: Cancer Science Volume: 110 Issue: 3 Pages: 867-874
  • DOI: 10.1111/cas.13919
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The era of immunogenomics/immunopharmacogenomics (2018)
  • Author(s): Zewde Makda、Kiyotani Kazuma、Park Jae-Hyun、Fang Hua、Yap Kai Lee、Yew Poh Yin、Alachkar Houda、Kato Taigo、Mai Tu H.、Ikeda Yuji、Matsuda Tatsuo、Liu Xiao、Ren Lili、Deng Boya、Harada Makiko、Nakamura Yusuke
  • Journal Title: Journal of Human Genetics Volume: 63 Issue: 8 Pages: 865-875
  • DOI: 10.1038/s10038-018-0468-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Immunoglobulin profiling identifies unique signatures in patients with Kawasaki disease during intravenous immunoglobulin treatment (2018)
  • Author(s): Ko Tai-Ming、Kiyotani Kazuma、Chang Jeng-Sheng、Park Jae-Hyun、Yin Yew Poh、Chen Yuan-Tsong、Wu Jer-Yuarn、Nakamura Yusuke
  • Journal Title: Human Molecular Genetics Volume: 27 Issue: 15 Pages: 2671-2677
  • DOI: 10.1093/hmg/ddy176
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer (2018)
  • Author(s): Santa-Maria Cesar August、Kato Taigo、Park Jae-Hyun、Kiyotani Kazuma、Rademaker Alfred、Shah Ami N.、Gross Leeaht、Blanco Luis Z.、Jain Sarika、Flaum Lisa、Tellez Claudia、Stein Regina、Uthe Regina、Gradishar William J.、Cristofanilli Massimo、Nakamura Yusuke、Giles Francis J.
  • Journal Title: Oncotarget Volume: 9 Issue: 27 Pages: 18985-18996
  • DOI: 10.18632/oncotarget.24867
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor?Engineered T Cells for Ovarian Cancer (2018)
  • Author(s): Matsuda Tatsuo、Leisegang Matthias、Park Jae-Hyun、Ren Lili、Kato Taigo、Ikeda Yuji、Harada Makiko、Kiyotani Kazuma、Lengyel Ernst、Fleming Gini F.、Nakamura Yusuke
  • Journal Title: Clinical Cancer Research Volume: 24 Issue: 21 Pages: 5357-5367
  • DOI: 10.1158/1078-0432.ccr-18-0142
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Comparison of TCR repertoires between cancer tissues and lymph nodes in colorectal cancer patients. (2019)
  • Author(s): Kiyotani K, Matsuda T, Miyauchi E, Hsu Y, Nagayama S, Zewde M, Park JH, Kato T, Harada M, Suzuki N, Nagano H, Hazama S, Nakamura Y.
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Identification of cancer-reactive/neoantigen-specific T cells in peripheral blood and tumor tissues of cancer patients. (2019)
  • Author(s): Kiyotani K
  • Organizer: 6th Annual Meeting of Colegio Mexicano para la Investigacion del Cancer
  • Int'l Joint Research / Invited
• [Presentation] Progress and future of cancer immunotherapy (2019)
  • Author(s): Kiyotani K
  • Organizer: 第78回日本癌学会
• [Presentation] Screening of cancer-reactive/neoantigen-specific T cells in peripheral blood and tumor tissues of cancer patients. (2019)
  • Author(s): Kiyotani K, Nakamura Y.
  • Organizer: 第78回日本癌学会
• [Presentation] Secreted PD-L1 variants caused by aberrant splicing mediate antiPD-L1 antibody resistance. (2019)
  • Author(s): Gong B, Kiyotani K, Sakata S, Nishio M, Takeuchi K, Kawamoto H, Fujita N, Katayama R.
  • Organizer: 第78回日本癌学会
• [Presentation] TCR repertoires in lung adenocarcinomas with and without EGFR mutation. (2019)
  • Author(s): Miyauchi E, Matsuda T, Kiyotani K, Low SK, Tsukita Y, Ichinose M, Sakurada A, Okada Y, Saito R, Nakamura Y.
  • Organizer: 第78回日本癌学会
• [Presentation] Clinical significance of clonal hematopoiesis in the interpretation of blood liquid biopsy. (2019)
  • Author(s): Chan HT, Nagayama S, Chin YM, Hayashi R, Kiyotani K, Nakamura Y, Low SK.
  • Organizer: 第78回日本癌学会
• [Presentation] NGSデータからのネオアンチゲン予測アルゴリズム開発および特異的T細胞の誘導 (2018)
  • Author(s): 清谷一馬
  • Organizer: 第31回日本バイオセラピィ学会学術集会総会
• [Presentation] TCR sequencing analysis of cancer tissues and lymph nodes in colorectal cancer patients (2018)
  • Author(s): Kiyotani K, Matsuda T, Nagayama S, Miyauchi E, Hsu Y, Zewde M, Park JH, Kato T, Harada M, Suzuki N, Nagano H, Hazama S, Nakamura Y
  • Organizer: 第77回日本癌学会
• [Presentation] Establishment of T-cell receptor-engineered T cells: Inplications for head and neck squemous carcinoma (2018)
  • Author(s): Ren L, Matsuda T, Deng B, Kiyotani K, Kato T, Park JH, Agrawal N, Nakamura Y
  • Organizer: 第77回日本癌学会
• [Presentation] T cell receptor repertoire analysis of lung adenocarcinoma harboring EGFR mutations (2018)
  • Author(s): Miyauchi E, Matsuda T, Hsu Y, Tsukita Y, Ichinose M, Sakurada A, Okada Y, Saito R, Kiyotani K, Nakamura Y
  • Organizer: 第77回日本癌学会