Immune response-associated gene expression profiling for biomarker development in hypermutated tumors

• Project/Area Number: 17K07209
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnostics
• Research Institution: Shizuoka Cancer Center Research Institute
• Principal Investigator: Akiyama Yasuto 静岡県立静岡がんセンター(研究所), その他部局等, 研究員 (70222552)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Hypermutator / 腫瘍内浸潤リンパ球 / T細胞受容体 / 次世代シークエンサー / がん免疫療法 / 高頻度遺伝子変異腫瘍 / がんエキソーム解析 / 免疫応答関連遺伝子 / 免疫チェックポイント抗体 / がんエクソーム解析 / 免疫学 / 癌 / ゲノム / マイクロアレイ

Outline of Final Research Achievements

Hypermutator tumors from 108 cancer patients with more than 500 SNV (20 TMB) were analyzed in terms of immune response-associated gene expression with aiming at the identification of biomarkers associated prognosis. In hypermutator tumors, specific T-cell activating genes, such as PD-L1, TNFSF9, IL-6, GZMB and CD3G, were upregulated in expression, which may suggest the functional activation of intratumoral T-cells. Hypermutator tumors with immune-inflamed signature (PD-L1+CD8+) showed a better prognosis compared with other immune types. Therefore, not only a hepermutation, but also the initiation of TIL induction against tumor-specific neoantigens in the tumor can be needed to obtaion a better cancer prognosis.

Academic Significance and Societal Importance of the Research Achievements

Hypermutator腫瘍は、PD-L1やTILマーカーと並んで免疫チェックポイント抗体治療の良好な予後を示唆するマーカーとして認知されている。しかし、これまでに多くの癌腫の患者において免疫チェックポイント抗体を用いた臨床試験が実施されてきているが、hypermutator腫瘍でも治療予後の悪い症例が少なからず存在する。治療前のhypermutator腫瘍内での免疫応答に関連する遺伝子の発現解析を行い、予後と相関するバイオマーカーを同定すればさらに治療予後の良い症例を選別することが可能となり、引いては抗体医療のコストパフォーマンスの改善にもつながると考えられる。

Research Products

• [Journal Article] Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients. (2020)
  • Author(s): Nagashima T, Yamaguchi K, Terashima M, et al.
  • Journal Title: Cancer Science Volume: 111 Issue: 2 Pages: 687-699
  • DOI: 10.1111/cas.14290
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of associations between clinical and immune microenvironmental factors and tumor mutation burden in resected nonsmall cell lung cancer by applying machine learning to whole-slide images. (2020)
  • Author(s): Ono A, Terada Y, Kawata T, Serizawa M, Isaka M, Kawabata T, Imai T, Mori K, Muramatsu K, Hayashi I, Kenmotsu H, Ohshima K, Urakami K, Nagashima T, Kusuhara M, Akiyama Y, Sugino T, Ohde Y, Yamaguchi K, Takahashi T.
  • Journal Title: Cancer Med. Volume: - Issue: 13 Pages: 4864-4875
  • DOI: 10.1002/cam4.3107
  • Peer Reviewed
• [Journal Article] Antitumor activity of the PD-1/PD-L1 binding inhibitor BMS-202 in the humanized MHC-double knockout NOG mouse (2019)
  • Author(s): Ashizawa T, Iizuka A, Tanaka E, Kondou R, Miyata H, Maeda C, Sugino T, Yamaguchi K, Ando T, Ishikawa Y, Ito M, Akiyama Y.
  • Journal Title: Biomedical Research Volume: 40 Issue: 6 Pages: 243-250
  • DOI: 10.2220/biomedres.40.243
  • NAID: 130007761178
  • ISSN: 0388-6107, 1880-313X
  • Year and Date: 2019-12-01
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a neoantigen epitope in a melanoma patient with good response to anti-PD-1 antibody therapy (2019)
  • Author(s): Nonomura C, Otsuka M, Kondou R, Iizuka A, Miyata H, Ashizawa T, Sakura N, Yoshikawa S, Kiyohara Y, Ohshima K, Urakami K, Nagashima T, Ohnami S, Kusuhara M, Mitsuya K, Hayashi N, Nakasu Y, Mochizuki T, Yamaguchi K, Akiyama Y
  • Journal Title: Immunol Lett Volume: 208 Pages: 52-59
  • DOI: 10.1016/j.imlet.2019.02.004
  • Peer Reviewed / Open Access
• [Journal Article] A T-cell-engaging B7-H4/CD3-bispecific Fab-scFv Antibody Targets Human Breast Cancer (2019)
  • Author(s): Iizuka Akira、Nonomura Chizu、Ashizawa Tadashi、Kondou Ryota、Ohshima Keiichi、Sugino Takashi、Mitsuya Koichi、Hayashi Nakamasa、Nakasu Yoko、Maruyama Kouji、Yamaguchi Ken、Akiyama Yasuto
  • Journal Title: Clinical Cancer Research Volume: 25 Issue: 9 Pages: 2925-2934
  • DOI: 10.1158/1078-0432.ccr-17-3123
  • Peer Reviewed / Open Access
• [Journal Article] Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy (2019)
  • Author(s): Hatakeyama K, Akiyama Y
  • Journal Title: Cancer Sci Volume: 110 Issue: 8 Pages: 2620-2628
  • DOI: 10.1111/cas.14087
  • Peer Reviewed
• [Journal Article] Imaging analysis of EGFR mutated cancer cells using peptide nucleic acid (PNA)?DNA probes (2019)
  • Author(s): Shigeto Hajime、Ohtsuki Takashi、Iizuka Akira、Akiyama Yasuto、Yamamura Shohei
  • Journal Title: The Analyst Volume: 144 Issue: 15 Pages: 4613-4621
  • DOI: 10.1039/c9an00725c
  • Peer Reviewed
• [Journal Article] Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors. (2019)
  • Author(s): Ohshima K, Fujiya K, Nagashima T, Ohnami S, Hatakeyama K, Urakami K, Naruoka A, Watanabe Y, Moromizato S, Shimoda Y, Ohnami S, Serizawa M, Akiyama Y, Kusuhara M, Mochizuki T, Sugino T, Shiomi A, Tsubosa Y, Uesaka K, Terashima M, Yamaguchi K.
  • Journal Title: Cancer Science Volume: 110 Issue: 12 Pages: 3821-3833
  • DOI: 10.1111/cas.14202
  • Peer Reviewed
• [Journal Article] Impact of combination therapy with anti-PD-1 blockade and a STAT3 inhibitor on the tumor-infiltrating lymphocyte status. (2019)
  • Author(s): Ashizawa T, Iizuka A, Maeda C, Tanaka E, Kondou R, Miyata H, Sugino T, Kawata T, Deguchi S, Mitsuya K, Hayashi N, Asai A, Ito M, Yamaguchi K, Akiyama Y.
  • Journal Title: Immunol Lett. Volume: 216 Pages: 43-50
  • DOI: 10.1016/j.imlet.2019.10.003
  • Peer Reviewed / Open Access
• [Journal Article] Classification of tumor microenvironment immune types based on immune response-associated gene expression (2019)
  • Author(s): Kondou R, Iizuka A, Nonomura C, Miyata H, Ashizawa T, Nagashima T, Ohshima K, Urakami K, Kusuhara M, Yamaguchi K, Akiyama Y
  • Journal Title: Int J Oncol Volume: 54 Pages: 219-228
  • DOI: 10.3892/ijo.2018.4617
  • Peer Reviewed / Open Access
• [Journal Article] <b>Tumor mutational burden analysis of 2,000 Japanese cancer genomes using whole exome and targeted gene panel </b><b>sequencing </b> (2018)
  • Author(s): Hatakeyama K, Nagashima T, Urakami K, Ohshima K, Serizawa M, Ohnami S, Shimoda Y, Ohnami S, Maruyama K, Naruoka A, Akiyama Y, Kusuhara M, Mochizuki T, Yamaguchi K
  • Journal Title: Biomedical Research Volume: 39 Issue: 3 Pages: 159-167
  • DOI: 10.2220/biomedres.39.159
  • NAID: 130007396436
  • ISSN: 0388-6107, 1880-313X
  • Year and Date: 2018-06-01
  • Peer Reviewed
• [Journal Article] Molecular profiling and sequential somatic mutation shift in hypermutator tumours harbouring POLE mutations (2018)
  • Author(s): Hatakeyama K, Ohshima K, Nagashima T, Ohnami S, Ohnami S, Serizawa M, Shimoda Y, Maruyama K, Akiyama Y, Urakami K, Kusuhara M, Mochizuki T, Yamaguchi K
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 8700-8700
  • DOI: 10.1038/s41598-018-26967-4
  • Peer Reviewed / Open Access
• [Journal Article] Changes in programmed death ligand 1 expression in non-small cell lung cancer patients who received anticancer treatments (2018)
  • Author(s): Omori S, Kenmotsu H, Abe M, Watanabe R, Sugino T, Kobayashi H, Nakashima K, Wakuda K, Ono A, TairaT, Naito T, Murakami H, Ohde Y, Endo M, Akiyama Y, Nakajima T, Takahashi T
  • Journal Title: Int J Clin Oncol Volume: 23 Issue: 6 Pages: 1052-1059
  • DOI: 10.1007/s10147-018-1305-4
  • Peer Reviewed
• [Journal Article] Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors. (2017)
  • Author(s): Ohshima K, Hatakeyama K, Nagashima T, Watanabe Y, Kanto K, Doi Y, Ide T, Shimoda Y, Tanabe T, Ohnami S, Ohnami S, Serizawa M, Maruyama K, Akiyama Y, Urakami K, Kusuhara M, Mochizuki T, Yamaguchi K
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 641-641
  • DOI: 10.1038/s41598-017-00219-3
  • Peer Reviewed / Open Access
• [Journal Article] The anti-tumor activity of the STAT3 inhibitor STX-0119 occurs via promotion of tumor-infiltrating lymphocyte accumulation in temozolomide-resistant glioblastoma cell line (2017)
  • Author(s): Akiyama Yasuto、Nonomura Chizu、Ashizawa Tadashi、Iizuka Akira、Kondou Ryota、Miyata Haruo、Sugino Takashi、Mitsuya Koichi、Hayashi Nakamasa、Nakasu Yoko、Asai Akira、Ito Mamoru、Kiyohara Yoshio、Yamaguchi Ken
  • Journal Title: Immunology Letters Volume: 190 Pages: 20-25
  • DOI: 10.1016/j.imlet.2017.07.005
  • Peer Reviewed
• [Journal Article] Sutureless microvascular anastomosis assisted by an expandable shape-memory alloy stent (2017)
  • Author(s): Saegusa Noriko、Sarukawa Shunji、Ohta Kunihiro、Takamatsu Kensuke、Watanabe Mitsuhiro、Sugino Takashi、Nakagawa Masahiro、Akiyama Yasuto、Kusuhara Masatoshi、Kishi Kazuo、Inoue Keita
  • Journal Title: PLOS ONE Volume: 12 Issue: 7 Pages: e0181520-e0181520
  • DOI: 10.1371/journal.pone.0181520
  • Peer Reviewed / Open Access
• [Journal Article] In situ delivery and production system of trastuzumab scFv with Bifidobacterium (2017)
  • Author(s): Kikuchi Takeshi、Shimizu Hitomi、Akiyama Yasuto、Taniguchi Shun'ichiro
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 493 Issue: 1 Pages: 306-312
  • DOI: 10.1016/j.bbrc.2017.09.026
  • Peer Reviewed / Open Access
• [Journal Article] Immune response-associated gene profiling in Japanese melanoma patients using multi-omics analysis (2017)
  • Author(s): Akiyama Yasuto、Kiyohara Yoshio、Yoshikawa Shusuke、Otsuka Masaki、Kondou Ryota、Nonomura Chizu、Miyata Haruo、Iizuka Akira、Ashizawa Tadashi、Ohshima Keiichi、Urakami Kenichi、Nagashima Takeshi、Kusuhara Masatoshi、Sugino Takashi、Yamaguchi Ken
  • Journal Title: Oncology Reports Volume: 39 Pages: 1125-1131
  • DOI: 10.3892/or.2017.6173
  • Peer Reviewed / Open Access
• [Presentation] 抗PD-1抗体療法が奏功したメラノーマ症例におけるネオアンチゲンの同定 (2019)
  • Author(s): 秋山靖人
  • Organizer: 第78回癌学会学術総会（京都）
• [Presentation] Characterization of hypermutated tumors based on tumor microenvironment immune types classification (2018)
  • Author(s): Akiyama Y, Iizuka A, Nagashima T, Shimoda Y, Tanabe T, Ohnami S, Ohnami S, Ohshima K, Urakami K, Kusuhara M, Mochizuki T, Yamaguchi K
  • Organizer: 第77回日本癌学会総会
• [Presentation] Classification of tumor microenvironment immune types based on the immune response-associated gene expression (2017)
  • Author(s): Akiyama Y, Iizuka A, Nagashima T, Shimoda Y, Tanabe T, Ohnami S, Ohnami S, Ohshima K, Urakami K, Kusuhara M, Mochizuki T, Yamaguchi K
  • Organizer: 第76回日本癌学会総会