T-Cell Receptor repertoire analyses in patients with esophageal cancer

• Project/Area Number: 16K10488
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Tohoku University
• Principal Investigator: Mori Takahiro 東北大学, 医学系研究科, 教授 (00323030)
• Co-Investigator(Kenkyū-buntansha): 安田 純 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), 発がん制御研究部, 部長 (00281684) ; 齋藤 さかえ 東北大学, 東北メディカル・メガバンク機構, 講師 (20335491)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 食道癌 / 化学放射線療法 / 腫瘍免疫 / 予後予測因子 / T細胞受容体遺伝子 / レパトア解析 / 放射線化学療法 / T細胞受容体 / 免疫多様性 / 治療効果 / TCRレパトア / 癌 / 外科 / 免疫学

Outline of Final Research Achievements

We analyzed TCR repertoire in patients with esophageal cancer who had been treated by chemoradiation (CRT). In 68 cases, genomic DNAs extracted from peripheral white blood cells were used for TCR repertoire. The obtained results suggested that cases with high TCR clonality have better prognosis. In 4 cases who had been treated primarily by CRT followed by surgery, mRNA extracted from tumors and normal mucosal tissues were used for repertoire analyses. The obtained results suggested that some T cell clones are shared both in tumors and mucosal tissues, which may represent Tumor Infiltrating Lymphocytes (TIL), and cases with less TILs had poor prognosis. Besides, cases after CRT had high clonality of TCR within tumors as compared to a case with surgery alone. These results suggested that tumor immunity should play an important role in CRT for esophageal cancers and that TCR repertoire could be prognostic marker candidate.

Academic Significance and Societal Importance of the Research Achievements

化学放射線療法（CRT）を施行された食道癌患者で腫瘍部と正常粘膜部に共通するユニークなT細胞クローンが存在すること（腫瘍への浸潤が少ないもので予後が８．５か月と不良）、末梢血でのクローナリティの高い症例ではCRT後の予後が良好であることが示唆された（p=0.103）。手術先行に比較してCRT後の切除例にクローナリティの高いという結果が得られた（Shannon 3.12±0.47, Simpson 14.9±5.77 ; 手術先行例ではShannon 5.72, Simpson 97.3）。このように、CRTの治療効果には腫瘍免疫が関与しており、本研究がCRTの予後予測に貢献できると考える。

Research Products

• [Journal Article] Construction of full-length Japanese reference panel of class I HLA genes with single-molecule, real-time sequencing (2018)
  • Author(s): Mimori T, Fumiki K, Sakae S、Naoki N, 、Akira O, Minegishi N, Kinoshita K, Nagasaki M, Yamamoto M
  • Journal Title: Pharmacogenomics Volume: 63 Issue: 2 Pages: 213-230
  • DOI: 10.1038/s41397-017-0010-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2,049 individuals (2018)
  • Author(s): Y Yamaguchi-Kabata, J Yasuda, O Tanabe, Y Suzuki, H Kawame, N Fuse, M Nagasaki, Y Kawai, K Kojima, F Katsuoka, S Saito, I Danjoh, I Motoike, R Yamashita, S Koshiba, D Saigusa, G Tamiya, S Kure, N Yaegashi, Y Kawaguchi, F Nagami, S Kuriyama, J Sugawara, N Minegishi, A Hozawa, T Takai-Igarashi, K Kinoshita, M Yamamoto.
  • Journal Title: Journal of Human Genetics. Volume: 63 Issue: 2 Pages: 213-230
  • DOI: 10.1038/s10038-017-0347-1
  • Peer Reviewed / Open Access
• [Journal Article] The G8 screening tool enhances prognostic value to ECOG performance status in elderly cancer patients: A retrospective, single institutional study. (2017)
  • Author(s): Takahashi M, Takahashi M, Komine K, Yamada H, Kasahara Y, Chikamatsu S, Okita A, Ito S, Ouchi K, Okada Y, Imai H, Saijo K, Shirota H, Takahashi S, Mori T, Shimodaira H, Ishioka C.
  • Journal Title: PLoS One. Volume: 12(6) Issue: 6 Pages: e0179694-e0179694
  • DOI: 10.1371/journal.pone.0179694
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficacy and safety of gemcitabine plus docetaxel in Japanese patients with unresectable or recurrent bone and soft tissue sarcoma: Results from a single-institutional analysis. (2017)
  • Author(s): Takahashi M, Komine K, Imai H, Okada Y, Saijo K, Takahashi M, Shirota H, Ohori H, Takahashi S, Chiba N, Mori T, Shimodaira H, Ishioka C.
  • Journal Title: PLoS One. Volume: 12(5) Issue: 5 Pages: e0176972-e0176972
  • DOI: 10.1371/journal.pone.0176972
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies (2017)
  • Author(s): Hachiya Tsuyoshi、Furukawa Ryohei、Shiwa Yuh、Ohmomo Hideki、Ono Kanako、Katsuoka Fumiki、Nagasaki Masao、Yasuda Jun、Fuse Nobuo、Kinoshita Kengo、Yamamoto Masayuki、Tanno Kozo、Satoh Mamoru、Endo Ryujin、Sasaki Makoto、Sakata Kiyomi、Kobayashi Seiichiro、Ogasawara Kuniaki、Hitomi Jiro、Sobue Kenji、Shimizu Atsushi
  • Journal Title: NPJ Genom Med. Volume: 2 Issue: 1 Pages: 0016-5
  • DOI: 10.1038/s41525-017-0016-5
  • Peer Reviewed / Open Access
• [Journal Article] Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7 (2017)
  • Author(s): Shiga Yukihiro、Kashiwagi Kenji、Nakazawa Toru、for the Japan Glaucoma Society Omics Group (JGS-OG)
  • Journal Title: PLOS ONE Volume: 12 Issue: 12 Pages: e0186678-e0186678
  • DOI: 10.1371/journal.pone.0186678
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing (2017)
  • Author(s): Shibuya Yusuke、Tokunaga Hideki、Saito Sakae、Shimokawa Kazurou、Katsuoka Fumiki、Bin Li、Kojima Kaname、Nagasaki Masao、Yamamoto Masayuki、Yaegashi Nobuo、Yasuda Jun
  • Journal Title: Genes Chromosomes Cancer. Volume: 57 Issue: 2 Pages: 51-60
  • DOI: 10.1002/gcc.22507
  • Peer Reviewed / Open Access
• [Journal Article] A Histologic Categorization of Aqueous Outflow Routes in Familial Open-Angle Glaucoma and Associations With Mutations in the MYOC Gene in Japanese Patients. (2017)
  • Author(s): Hamanaka T, Kimura M, Sakurai T, Ishida N, Yasuda J, Nagasaki M, Nariai N, Endo A, Homma K, Katsuoka F, Matsubara Y, Yamamoto M, Fuse N.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 58 Issue: 5 Pages: 2818-2831
  • DOI: 10.1167/iovs.16-20646
  • Peer Reviewed / Open Access