Analysis of Predictive Biomarkers for Immune Checkpoint Inhibitors in Lung Adenocarcinoma

• Project/Area Number: 16K10691
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Juntendo University
• Principal Investigator: Takamochi Kazuya 順天堂大学, 医学部, 准教授 (30397369)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肺腺癌 / 免疫治療 / 免疫チェックポイント阻害薬 / バイオマーカー / 非小細胞肺癌 / 腫瘍免疫 / 肺扁平上皮癌 / 免疫関連分子 / ドライバー遺伝子 / MSI / 免疫学

Outline of Final Research Achievements

Programmed death 1 (PD-1), and its associated ligand (PD-L1) checkpoint blockade immunotherapy caused a new paradigm shift in treatment for patients with non-small cell lung cancer (NSCLC). Appropriate patient selection is critically important. To identify predictive biomarkers immune checkpoint inhibitors, we comprehensively analyzed previously reported predictive biomarkers such as smoking status, driver oncogene alterations, PD-L1 expression, MSI and tumor immune microenvironment, and clarified the reciprocal relationship among them. We showed that MSI is a rare event in lung adenocarcinoma. MSI cannot be used as a biomarker to predict the treatment effect of immune checkpoint inhibitors for lung adenocarcinoma. NSCLCs can be divisible into immunoreactive and non-immunoreactive tumors. The prognostic value differs according to the immunomodulatory target and driver oncogene status.

Academic Significance and Societal Importance of the Research Achievements

肺腺癌における腫瘍局所免疫状態を包括的に解析することによって、喫煙歴、ドライバー遺伝子変異の有無、肺腺癌の組織亜型、組織学的浸潤の程度などによって、免疫関連分子の発現状態が異なることが明らかになった。本研究の成果は今後、日常臨床で有用な免疫チェックポイント阻害薬の効果予測バイオマーカーを絞り込んでいく上で、貴重な基礎データとなった。

Research Products

• [Journal Article] Prognostic impacts of EGFR mutation status and subtype in patients with surgically resected lung adenocarcinoma. (2017)
  • Author(s): Takamochi K, Oh S, Matsunaga T, Suzuki K.
  • Journal Title: J Thorac Cardiovasc Surg. Volume: 154 Issue: 5 Pages: 1768-1774
  • DOI: 10.1016/j.jtcvs.2017.06.062
  • Peer Reviewed / Open Access
• [Journal Article] A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer (2017)
  • Author(s): Kohsaka Shinji、Nagano Masaaki、Ueno Toshihide、Suehara Yoshiyuki、Hayashi Takuo、Shimada Naoko、Takahashi Kazuhisa、Suzuki Kenji、Takamochi Kazuya、Takahashi Fumiyuki、Mano Hiroyuki
  • Journal Title: Science Translational Medicine Volume: 9 Issue: 416 Pages: 6566-6566
  • DOI: 10.1126/scitranslmed.aan6566
  • Peer Reviewed / Open Access
• [Journal Article] DNA mismatch repair deficiency in surgically resected lung adenocarcinoma: Microsatellite instability analysis using the Promega panel (2017)
  • Author(s): Takamochi Kazuya、Takahashi Fumiyuki、Suehara Yoshiyuki、Sato Eiichi、Kohsaka Shinji、Hayashi Takuo、Kitano Shigehisa、Uneno Toshihide、Kojima Shinya、Takeuchi Kengo、Mano Hiroyuki、Suzuki Kenji
  • Journal Title: Lung cancer Volume: 110 Pages: 26-31
  • DOI: 10.1016/j.lungcan.2017.05.016
  • Peer Reviewed / Open Access
• [Journal Article] Novel biomarkers that assist in accurate discrimination of squamous cell carcinoma from adenocarcinoma of the lung (2016)
  • Author(s): Takamochi, Kazuya;Ohmiya, Hiroko;Itoh, Masayoshi;Mogushi, Kaoru;Saito, Tsuyoshi;Hara, Kieko;Mitani, Keiko;Kogo, Yasushi;Yamanaka, Yasunari;Kawai, Jun;Hayashizaki, Yoshihide;Oh, Shiaki;Suzuki, Kenji;Kawaji, Hideya
  • Journal Title: BMC CANCER Volume: 16 Issue: 1 Pages: 760-760
  • DOI: 10.1186/s12885-016-2792-1
• [Presentation] Comprehensive analysis for immune profiles of tumor microenvironment in lung adenocarcinomas: Prognostic effect of immunomodulatory molecules. (2018)
  • Author(s): Kazuya Takamochi, Masaki Hosoya, Kaoru Mogushi, Takuo Hayashi, Masayoshi Ito, Hideya Kawaji, Yoshihide Hayashizaki, Kenji Suzuki
  • Organizer: ESMO MAP
  • Int'l Joint Research
• [Presentation] Comprehensive analysis for immune profiles of tumor microenvironment in non-small cell lung cancers: Prognostic effect of immunomodulatory molecules. (2018)
  • Author(s): Kazuya Takamochi, Masaki Hosoya, Kaoru Mogushi, Takuo Hayashi, Masayoshi Ito, Hideya Kawaji, Yoshihide Hayashizaki, Kenji Suzuki
  • Organizer: ESMO
  • Int'l Joint Research
• [Presentation] The PD-L1 expression in surgically resected lung adenocarcinoma: Its correlations with the prognosis, driver oncogene alterations and clinicopathological features. (2018)
  • Author(s): Kazuya Takamochi, Takuo Hayashi, Kieko Hara, Kenji Suzuki
  • Organizer: ESMO Asia
  • Int'l Joint Research
• [Presentation] 肺腺癌における免疫関連分子の包括的遺伝子発現解析. (2018)
  • Author(s): 高持一矢、細谷理樹、茂櫛 薫、林 大久生、川路英哉、伊藤昌可、林崎良英、鈴木健司
  • Organizer: 日本肺癌学会
• [Presentation] Practical screening system of oncogenic driver fusions in lung adenocarcinoma, using the NanoString nCounter (2017)
  • Author(s): Kazuya Takamochi, Yoshiyuki Suehara, Fumiyuki Takahashi, Kaoru Mogushi, Shinji Kohsaka, Hiroyuki Mano, Kengo Takeuchi, Tsuyoshi Saito, Takuo Hayashi, Kazuhisa Takahashi, Kenji Suzuki
  • Organizer: ESMO MAP
  • Int'l Joint Research
• [Presentation] NanoString nCounterを用いた肺腺癌におけるドライバー融合遺伝子の効率的スクリーニングシステムの開発 (2017)
  • Author(s): 高持一矢、王 志明、松永健志、鈴木健司
  • Organizer: 第70回日本胸部外科学会定期学術集会
• [Presentation] 肺腺癌切除例におけるEGFR遺伝子変異の有無、EGFR遺伝子変異タイプの予後因子としての意義 (2016)
  • Author(s): 高持一矢、王 志明、松永健志、鈴木健司
  • Organizer: 第57回日本肺癌学会学術集会
  • Place of Presentation: 福岡, 福岡国際会議場, 福岡サンパレス
  • Year and Date: 2016-12-19
• [Presentation] The prognostic impact of EGFR mutation status and mutation subtypes in patients with surgically resected lung adenocarcinomas (2016)
  • Author(s): Kazuya Takamochi, Shiaki Oh, Takeshi Matsunaga, Kenji Suzuki
  • Organizer: 17th WCLC
  • Place of Presentation: Vienna, Messe Wien Exhibition & Congress Center
  • Year and Date: 2016-12-04
• [Presentation] A microsatellite instability analysis using the Promega panel in lung adenocarcinoma (2016)
  • Author(s): Kazuya Takamochi, Fumiyuki Takahashi, Yoshiyuki Suehara, Shigehisa Kitano, Eiichi Sato, Shinji Kohsaka, Kenji Suzuki "
  • Organizer: CHEST
  • Place of Presentation: Los Angeles, Los Angeles Convention Center
  • Year and Date: 2016-10-22
• [Presentation] A microsatellite instability analysis using the Promega panel in lung adenocarcinoma (2016)
  • Author(s): Kazuya Takamochi, Fumiyuki Takahashi, Yoshiyuki Suehara, Shigehisa Kitano, Eiichi Sato, Shinji Kohsaka, Kenji Suzuki
  • Organizer: 第14回日本臨床腫瘍学会学術集会
  • Place of Presentation: 神戸, 神戸国際会議場
  • Year and Date: 2016-07-28