Enhancement of anti-tumor immune responses by EGFR-TKIs (EGFR- tyrosin kinase inhibitors)

• Project/Area Number: 25830122
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Keio University
• Principal Investigator: YAGUCHI Tomonori 慶應義塾大学, 医学部, 助教 (40424163)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: がん免疫療法 / 肺癌 / EGFR-TKI / 免疫抑制

Outline of Final Research Achievements

In this study, we evaluated the enhancement of anti-tumor immune responses by EGFR-tyrosine kinase inhibitor (TKI) in non-small cell lung carcinoma cell (NSCLC). Human NSCLC with mutated EGFR produced immunosuppressive cytokines and suppressed human DC function, which were restored by EGFR-TKI pretreatment of NSCLC. EGFR-TKI directly enhanced human DC function in an EGFR-independent manner. Moreover, in vivo administration of EGFR-TKI augmented tumor antigen-specific T cell induction and enhanced anti-tumor effects of immunotherapies. These results indicate that EGFR-TKIs may have an activity to enhance antitumor immune responses for NSCLC by targeting both cancer cells and DC, and combined use of EGFR-TKIs may augment the therapeutic effects of current immunotherapies.

Research Products

• [Journal Article] Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor. (2014)
  • Author(s): Nishio H, Yaguchi T, Sugiyama J, Sumimoto H, Umezawa K, Iwata T, Susumu N,Fujii T, Kawamura N, Kobayashi A, Park J, Aoki D, Kawakami Y.
  • Journal Title: Br J Cancer. Volume: 110 Issue: 12 Pages: 2965-74
  • DOI: 10.1038/bjc.2014.251
  • Peer Reviewed / Open Access
• [Journal Article] TGF-β1 in tumor microenvironments induces immunosuppression in the tumors and sentinel lymph nodes and promotes tumor progression (2014)
  • Author(s): Nakamura S, Yaguchi T, Kawamura N, Kobayashi A, Sakurai T, Higuchi H, Takaishi H, Hibi T, Kawakami Y
  • Journal Title: J Immunother Volume: 37(2) Issue: 2 Pages: 63-72
  • DOI: 10.1097/cji.0000000000000011
  • Peer Reviewed / Open Access
• [Journal Article] 抗腫瘍免疫応答の総合的な制御 (2014)
  • Author(s): 谷口智憲，河上裕.
  • Journal Title: 血液フロンティア Volume: 24 Pages: 1579-1605
• [Journal Article] がんの免疫逃避機構と分子標的薬を用いた免疫応答の制御 (2014)
  • Author(s): 谷口智憲, 河上裕
  • Journal Title: 産科と婦人科 Volume: 81 Pages: 157-163
• [Journal Article] がん免疫における免疫チェックポイント機構の意義とその制御によるがん治療 (2014)
  • Author(s): 河上裕 川村直 ポピバノバ・ボリヤナ 中村謙太 早川妙香 谷口智憲
  • Journal Title: がん分子標的治療 Volume: 12 Pages: 15-22
• [Journal Article] Intratumoral Injection of BCG-CWS-Pretreated Dendritic Cells Following Tumor Cryoablation (2014)
  • Author(s): Kawamura N, Udagawa M, Fujita T, Sakurai T, Yaguchi T, Kawakami Y.
  • Journal Title: Methods Mol Biol. Volume: 1139 Pages: 145-53
  • DOI: 10.1007/978-1-4939-0345-0_13
  • ISBN: 9781493903443, 9781493903450
  • Peer Reviewed
• [Journal Article] 化学療法・分子標的薬による免疫応答増強 (2013)
  • Author(s): 谷口智憲、河上裕
  • Journal Title: 医学のあゆみ Volume: 244 Pages: 817-823
• [Journal Article] 化学療法・分子標的薬による抗腫瘍免疫応答の制御 (2013)
  • Author(s): 谷口智憲, 里見良輔、西尾浩、杉山重里、大村学、中村謙太、川村直、小林明日香、河上裕
  • Journal Title: 実験医学 Volume: 31 Pages: 1938-1944
• [Journal Article] 悪性黒色腫におけるPI3K/AKT経路の役割 (2013)
  • Author(s): 谷口智憲, 川村直, 中村謙太, 河上裕
  • Journal Title: 日本臨床 Volume: 71 suppl 4 Pages: 139-143
• [Journal Article] 抗PD-1抗体、抗PD-L1抗体による免疫療法 (2013)
  • Author(s): 谷口智憲, 里見良輔, 川村直, 河上裕
  • Journal Title: 日本臨床 Volume: 71 suppl 6 Pages: 253-257
• [Journal Article] Cancer-induced immunosuppressive cascades and their reversal by molecular-targeted therapy. (2013)
  • Author(s): Kawakami Y, Yaguchi T, Sumimoto H, Kudo-Saito C, Tsukamoto N, Iwata-Kajihara T, Nakamura S, Nishio H, Satomi R, Kobayashi A, Tanaka M, Hoon Park J, Kamijuku H, Tsujikawa T, Kawamura N
  • Journal Title: Ann. N.Y. Acad. Sci., Volume: 1284(1) Issue: 1 Pages: 80-86
  • DOI: 10.1111/nyas.12094
  • Peer Reviewed
• [Journal Article] Improvement of cancer immunotherapy by combining molecular targeted therapy (2013)
  • Author(s): Kawakami Y, Yaguchi T, Sumimoto H, Kudo-Saito C, Iwata-Kajihara T, Nakamura S, Miyzaki J, Kawamura N, Hoon Park J, Popivanova B, Tsujikawa T
  • Journal Title: Frontiers in Oncology Volume: 36 Pages: 1-7
  • DOI: 10.3389/fonc.2013.00136
  • Peer Reviewed
• [Journal Article] Angiotensin II type 1 receptor antagonist attenuates lacrimal gland, lung, and liver fibrosis in a murine model of chronic graft-versus-host disease. (2013)
  • Author(s): Yaguchi S, Ogawa Y, Shimmura S, Kawakita T, Hatou S, Satofuka S, Nakamura S, Imada T, Miyashita H, Yoshida S, Yaguchi T, Ozawa Y, Mori T, Okamoto S, Kawakami Y, Ishida S, Tsubota K.
  • Journal Title: PLoS ONE Volume: 8 Issue: 6 Pages: e64724-e64724
  • DOI: 10.1371/journal.pone.0064724
  • Peer Reviewed
• [Presentation] Effective cancer immunotherapy for human melanoma by combination of BRAF inhibitor and Toll-like receptor 7 agonist (2014)
  • Author(s): Nakamura K, Yaguchi T, Popivanova B, Murata M, Mikoshiba A, Kiniwa Y, Okuyama R, Kawakami Y
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] EGFR-TKIs (EGFR- tyrosin kinase inhibitors) enhance anti-tumor immune responses by acting on both non-small cell lung carcinoma cells and immune cells (2014)
  • Author(s): Yaguchi T, Satomi R, Kobayashi A, Morii K, Kawakami Y.
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Enhanced anti-tumor effects of the PD-1/PD-L1 blockade by combining a highly absorptive form of NF-kB/STAT3 inhibitor curcumin (2014)
  • Author(s): Hayakawa T, Sugiyama J, Yaguchi T, Imaizumi A, Kawakami Y.
  • Organizer: Society for Immunotherapy of Cancer 29th Annual Meeting
  • Place of Presentation: National Harbor, MD, USA.
  • Year and Date: 2014-11-06 – 2014-11-09
• [Presentation] 分子標的薬併用による効果的な個別化がん免疫療法 (2014)
  • Author(s): 河上 裕、早川 妙香、中村 謙太、ボリヤナ ポピバノバ、杉山 重里、西尾 浩、谷口 智憲
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] ルクミン併用による免疫抑制改善効果を介した免疫チェックポイント阻害療法の効果増強 (2014)
  • Author(s): 早川 妙香、杉山 重里、谷口 智憲、今泉 厚、河上 裕
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] CD155-TIGIT interaction is an immune checkpoint regulating antimelanoma immune responses (2014)
  • Author(s): 猪爪隆史、谷口智憲、古田潤平、原田和俊、伊藤守、河上裕、島田眞路
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: 松山
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] ヒト末梢血移入マウスMHC class I/IIノックアウトNOGマウスを用いたヒト腫瘍免疫応答のin vivo解析 (2014)
  • Author(s): 谷口智憲、小林明日香、片野いくみ、何裕遥、猪爪隆史、伊藤守、河上裕
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: 松山
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] 高吸収性クルクミン併用による免疫抑制改善効果を介した免疫チェックポイント阻害療法の効果増強 (2014)
  • Author(s): 早川妙香、杉山重里、今泉厚、谷口智憲、河上裕
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: 松山
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] 局所性Renin-Angiotensin systemの阻害による、がん関連線維芽細胞や骨髄系免疫細胞の制御を介したPD-1/PD-L1免疫チェックポイント阻害療法の効果増強 (2014)
  • Author(s): 中村謙太、谷口智憲、大村学、小林明日香、川村直、杉山重里、桜井敏晴、木庭幸子、奥山隆平、河上裕
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: 松山
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] 悪性黒色腫に異所性に発現するHistatin-1は樹状細胞を抑制し、がん免疫回避に関与する (2013)
  • Author(s): 谷口智憲、栗原智樹、後藤康文、伊藤有毅、守井賢二、小林明日香、西尾浩、住本秀敏、河上裕
  • Organizer: 第23回 日本樹状細胞研究会
  • Place of Presentation: 京都、京都、日本
• [Presentation] 局所性Renin-Angiotensin systemは免疫抑制的がん微小環境の構築に関与する (2013)
  • Author(s): 中村 謙太、谷口 智憲、大村 学、小林 明日香、川村 直、杉山 重里、桜井 敏晴、木庭 幸子、奥山 隆平、河上 裕
  • Organizer: 第17回 日本がん免疫学会総会
  • Place of Presentation: 宇部、山口、日本
• [Presentation] ヒト卵巣明細胞腺癌に発現するHNF-1βは免疫抑制的がん微小環境の構築に関与する (2013)
  • Author(s): 杉山重里、 谷口智憲、 川村直、 中村謙太、 大村学、 岩田卓、 藤田知信、 青木大輔、河上裕
  • Organizer: 第17回 日本がん免疫学会総会
  • Place of Presentation: 宇部、山口、日本
• [Presentation] EGFR-TKIs (EGFR-tyrosin kinase inhibitors)は非小細胞肺癌と免疫担当細胞の両者に作用し抗腫瘍免疫応答を増強させる (2013)
  • Author(s): 里見良輔、谷口智憲、 小林 明日香、副島研造、別役智子、河上裕
  • Organizer: 第17回 日本がん免疫学会総会
  • Place of Presentation: 宇部、山口、日本
• [Presentation] EGFR-TKIs (EGFR-tyrosin kinase inhibitors) enhance anti-tumor immune responses in an EGFR independent manner (2013)
  • Author(s): Yaguchi T, Satomi R, Kobayashi A, Soejima K, Betsuyaku T, Kawakami Y
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: 横浜、神奈川、日本
• [Presentation] HNF-1β is an upstream molecule in immunosuppression by human ovarian clear cell carcinoma (OCCC) (2013)
  • Author(s): Sugiyama J, Yaguchi T, Kawamura N, Nakamura K, Ohmura G. Iwata T, Fujita T, Aoki D, Kawakami Y
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: 横浜、神奈川、日本
• [Presentation] Immunosuppressive roles of local renin–angiotensin system (RAS) in cancer microenvironments (2013)
  • Author(s): Nakamura K, Yaguchi T, Ohmura G. Kobayashi A Kawamura N, Sugiyama J, Sakurai T, Kiniwa Y, Okuyama R, Kawakami Y
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: 横浜、神奈川、日本
• [Presentation] Reversal of immunosuppression in ovarian cancer microenvironment by targeting NF-kB signal and its clinical application (2013)
  • Author(s): Nishio H, Yaguchi T, Sumimoto H, Umezawa K, Sugiyama J, Iwata T, Aoki D, Kawakami Y
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: 横浜、神奈川、日本
• [Presentation] Myosin 1bは頭頸部癌で過剰発現し、腫瘍細胞の浸潤・遊走・転移を促進する (2013)
  • Author(s): 大村学、辻川敬裕、谷口智憲、川村直、中村謙太、杉山重里、三上修治、中野宏、島田剛敏、久育男、河上裕
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: 横浜、神奈川、日本
• [Presentation] NF-kBシグナルを標的とした卵巣癌局所における免疫抑制環境の改善と治療への応用 (2013)
  • Author(s): 岩田卓、田中京子、杉山重里、西尾浩、平尾薫丸、森定徹、早川妙香、谷口智憲、河上裕、青木大輔
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: 横浜、神奈川、日本
• [Presentation] Systemic administration of a highly absorptive form of curcumin reverses cancer-induced immunosuppression through inhibiting NF-kB and STAT3 (2013)
  • Author(s): Hayakawa T, Sugiyama J, Yaguchi T, Imaizumi A, Kawakami Y
  • Organizer: 第42回 日本免疫学会総会
  • Place of Presentation: 幕張、千葉、日本
• [Presentation] Human PBMC transferred murine MHC class I/II deficient NOG mice are useful for analysis of human T/B cell responses (2013)
  • Author(s): Yaguchi T, Kobayashi A, Ka Y, Katano I, Ito M, Kawakami Y
  • Organizer: 第42回 日本免疫学会総会
  • Place of Presentation: 幕張、千葉、日本
• [Presentation] MHC class I/II deficient NOG mice are useful for analysis of human T/B cell responses for human tumor immunology research (2013)
  • Author(s): Yaguchi T, Kobayashi A, Ka Y, Katano I, Ito M, Kawakami Y
  • Organizer: SiTC 2013 28th annual meeting
  • Place of Presentation: National Harbor, MD, USA
• [Presentation] がん微小環境における抑制性免疫細胞の誘導とその制御 (2013)
  • Author(s): 谷口 智憲、中村 謙太、杉山 重里、西尾 浩、川村 直、里見 良輔、河上 裕
  • Organizer: 第41回 臨床免疫学会総会
  • Place of Presentation: 下関、山口、日本
  • Invited