Novel cancer immunotherapy targeting neoantigens in combination with epigenetics and immune modulation
| Project/Area Number |
16H04708
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Kakimi Kazuhiro 東京大学, 医学部附属病院, 特任教授 (80273358)
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| Co-Investigator(Kenkyū-buntansha) |
松下 博和 東京大学, 医学部附属病院, 特任講師 (80597782)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2018: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2017: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2016: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
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| Keywords | ネオアンチゲン / エピゲノム / がん免疫 / DNAメチル化阻害剤 / HDAC阻害剤 / 胃癌 / 肺癌 / メラノーマ / マウスモデル / DNAメチル基転移酵素(DNMT)阻害剤 / DNMT阻害剤 / 腫瘍免疫 / 遺伝子変異 / がん抗原 / 次世代シーケンサー / エピトープ / 免疫学 |
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| Outline of Final Research Achievements |
Neoantigens were identified by NGS analysis in 4 cancer cell lines, YTN2, YTN16, LLC1 and B16, that can be studied in tumor-bearing mice model. These 4 cell lines were treated with DNMT inhibitors, 5-Azacytidine and Decitabine, and HDAC inhibitors, Vorinostat, Trichostatin A, Panobinostat and Valproic acid to modify the gene expression of neoantigens by regulation of epigenetic modification. By this treatment, gene expression of one neoantigen increased to 1000 times. Trichostatin A induced gene expression of 12 neoantigens out of 18 neoantigens that lacked expression without treatment. These results indicate that the epigenetic modification of neoantigen can be used for the potentiation of anti-tumor immunity.
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| Academic Significance and Societal Importance of the Research Achievements |
免疫チェックポイント阻害剤による癌治療は、腫瘍の進展の過程で蓄積される腫瘍特異的遺伝子変異抗原(ネオアンチゲン)に対する内因性免疫を活性化している。これからのがん免疫治療は、ネオアンチゲンを標的として、免疫抑制解除を併用する複合的ながん免疫治療が主流になると考えられるが、Exomeシークエンスの情報から同定されたネオアンチゲンは必ずしもがん細胞において発現している訳ではない。そこでDNMT阻害剤やHDAC阻害剤を用いたエピジェネティック治療を併用し、がん細胞におけるネオアンチゲンの発現を回復させ、ネオアンチゲン特異的な免疫応答を誘導し増強させることで革新的ながん免疫治療創出が期待される。
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Report
(4 results)
Research Products
(50 results)
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[Journal Article] High CCR4 expression in the tumor microenvironment is a poor prognostic indicator in lung adenocarcinoma.2018
Author(s)
Karasaki T, Qiang G, Anraku M, Sun Y, Shinozaki-Ushiku A, Sato E, Kashiwabara K, Nagayama K, Nitadori JI, Sato M, Murakawa T, Kakimi K, Fukayama M, Nakajima J.
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Journal Title
J Thorac Dis
Volume: 10
Issue: 8
Pages: 4741-4750
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma.2017
Author(s)
Matsushita H, Hasegawa K, Oda K, Yamamoto S, Nishijima A, Imai Y, Asada K, Ikeda Y, Karasaki T, Fujiwara K, Aburatani H, Kakimi K.
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Journal Title
Oncoimmunology
Volume: 6
Issue: 8
Pages: e1338996-e1338996
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Prediction and prioritization of neoantigens: integration of RNA sequencing data with whole-exome sequencing.2017
Author(s)
Karasaki T, Nagayama K, Kuwano H, Nitadori JI, Sato M, Anraku M, Hosoi A, Matsushita H, Takazawa M, Ohara O, Nakajima J, Kakimi K.
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Journal Title
Cancer Sci.
Volume: 108(2)
Issue: 2
Pages: 170-177
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Presentation] Neoantigen load and HLA-class I expression characterize a subset of HR-proficient high-grade serous ovarian carcinomas with favorable prognosis and T cell-inflamed phenotype.2018
Author(s)
Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi oda, Shogo Yamamoto, Kayo Asada, Akira Yabuno, Akira Nishijima, Takahiro krasaki, Yuji Ikeda, Keiichi Fujiwara, Hiroyuki Aburatani, Kazuhito Kakimi.
Organizer
AACR (American Association for Cancer Research) Annual Meeting 2018
Related Report
Int'l Joint Research
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[Presentation] Neoantigen frequency as an independent prognostic factor in patients with clear ovarian carcinoma(CCOC)2017
Author(s)
Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi Oda, Shogo Yamamoto, Akira Nishijima, Yuichi Imai, Kayo Asada, Yuji Ikeda, Takahiro Karasaki, Keiichi Fujiwara, Hiroyuki Aburatani, Kazuhiro Kakimi,
Organizer
AACR (American Association for Cancer Research) Annual Meeting 2017
Related Report
Int'l Joint Research
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[Presentation] Immunogram for Cancer-Immunity Cycle towards Personalized Immunotherapy of Lung Cancer2016
Author(s)
Takahiro Karasaki, Kazuhiro Nagayama, Hideki Kuwano, Jun-ichi Nitadori, Masaaki Sato, Masaki Anraku, Akihiro Hosoi, Hirokazu Matsushita, Yasuyuki Morishita, Kosuke Kashiwabara, Masaki Takazawa, Osamu Ohara, Kazuhiro Kakimi, Jun Nakajima
Organizer
IASLC 17th World Conference on Lung Cancer
Place of Presentation
Vienna, Austria
Related Report
Int'l Joint Research
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