A novel antitumor immunotherapy to break the tolerance induced in small cell lung cancer patients

• Project/Area Number: 18590841
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Niigata University
• Principal Investigator: KAGAMU Hiroshi Niigata University, Institute of Medicine and Dentistry, Assistant Professor (30418686)
• Co-Investigator(Kenkyū-buntansha): NAKATA Koh Niigata University, Medical and Dental Hospital, Professor (80207802) ; YOSHIZAWA Hirohisa Niigata University, Medical and Dental Hospital, Associate Professor (50282984)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,690,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: small cell lung cancer / regulatory T cell / antitumor effector CD4 T cell / 抗腫瘍エフェクターCD4T細胞

Research Abstract

Small cell lung cancer (SCLC) possesses high tendency to disseminate. However, SCLC patients with paraneoplastic syndrome mediated by immunity against onconeural antigens remain in limited-stage disease (LD) without distant metastases. Cumulative evidence regulates that a balance between immune and regulatory T cells (Treg) determines the magnitude of immune responses to not only self-antigens but also tumor-associated antigens. Here, we analyzed T cells in the peripheral blood of 35 consecutive SCLC patients, 8 long-term survivors, and 19 healthy volunteers to assess the balance of CD4^+ T cells. Purified CD4^+ T cells with down-regulated expression of CD62L (CD62L^(low)) produced IFN-γ, IL-4, and IL-17, thus, considered to be immune effector T cells (Teff). Significantly more Teff numbers were detected in LD-SCLC patients than that of extended-stage SCLC (ED-SCLC). By contrast, induction of CD62L^(high) CD25^+ CD4^+ Treg was significantly higher in ED-SCLC patients than that of LD-SCLC patients. Analyses of cytokine secretion revealed that Teff in LD-SCLC patients produced significantly more IL-17 and that dendritic cells derived from CD14^+ cells of LD-SCLC patients secreted more IL-23. Long-term survivors of SCLC maintained a high Teff to Treg ratio, whereas patients with recurrent disease exhibited a low Teff to Treg ratio. Therefore, we concluded that CD4^+ T cell balance may be a biomarker that distinguishes ED-SCLC from LD-SCLC and predicts recurrence. This study also suggests the importance of inducing effector CD4^+ T cells, particularly Th17 cells, while eliminating Treg to control systemic dissemination of SCLC.

Research Products

• [Journal Article] Appropriate timing of CD40 ligation for RNA-pulsed DCs to induce antitumor immunity (2008)
  • Author(s): Satoshi Miura, Hiroshi Kagamu, Hiroshi Tanaka, Hirohisa Yoshizawa, Fumitake Gejyo
  • Journal Title: Scandinavian Journal of Immunology 67 Pages: 385-391
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Appropriate timing of CD40 ligation for RNA-pulsed DCs to induce antitumor immunity (2008)
  • Author(s): Satoshi, Miura, Hiroshi, Kagamu, Hiroshi, Tanaka, Hirohisa, Yoshizawa, Fumitake, Gejyo
  • Journal Title: Scandinavian Journal of Immunology 67 Pages: 385-391
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Generation of anti-tumor effctor T cells from naive T cells by stimulation with dendritic/tumor fusion cells. (2007)
  • Author(s): Akira Ishida, Hiroshi Tanaka, Toru Hiura, Satoshi Miura, Satoshi Watanabe, Koki Matsuyama, Hideyuki Kuriyama, Junta Tanaka, Hiroshi Kagamu, Fumitake Gejyo, Hirohisa Yoshizawa
  • Journal Title: Scandinavian Journal of Immunology 66 Pages: 546-554
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Anti-cytokine autoantibodies are ubiquitous in healthy individuals (2007)
  • Author(s): Masato Watanabe, Kanji Uchida, Kazuhide Nakagaki, Hiroko Kanazawa, Bruce C. Trapnell, Yoshihiko Hoshino, Hiroshi Kagamu, Hirohisa Yoshizawa, Naoto Keicho, Hajime Goto, Koh Nakata
  • Journal Title: FEBS letters 581 Pages: 2017-2021
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Generation of anti-tumor effector T cells from naive T cells by stimulation with dendritic/tumor fusion cells (2007)
  • Author(s): Akira, Ishida, Hiroshi, Tanaka, Toru, Hiura, Satoshi, Miura, Satoshi, Watanabe, Koki, Matsuyama, Hideyuki, Kuriyama, Junta, Tanaka, Hiroshi, Kagamu, Fumitake, Geiyo, Hirohisa, Yoshizawa
  • Journal Title: Scandinavian Journal of Immunology 66 Pages: 546-554
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Anti-cytokine autoantibodies are ubiquitous in healthy individuals (2007)
  • Author(s): Masato, Watanabe., Kanji, Uchida., Kazuhide. Nakagaki., Hiroko. Kanazawa., Bruce C, Trapnell., Yoshihiko. Hoshino, Hiroshi. Kagamu, Hirohisa. Yoshizawa, Naoto. Keicho, Hajime. Goto, Koh. Nakata
  • Journal Title: FEBS letters 581 Pages: 2017-2021
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Generation of anti-tumor effector T cells from naive T cells by stimulation with dendritic/tumor fusion cells. (2007)
  • Author(s): Akira Ishida, Hiroshi Tanaka, Toru Hiura, Satoshi Miura, Satoshi Watanabe, Koki Matsuyama, Hideyuki Kuriyama, Junta Tanaka, Hiroshi Kagamu, Fumitake Gejyo, Hirohisa Yoshizawa
  • Journal Title: Scandinavian Journal of Immunology 66 Pages: 546-554
  • Peer Reviewed
• [Presentation] CD4+effector T cells specific for irrelevant peptides can induce antitumor reactivity via epitope spreading (2007)
  • Author(s): 小山建一、各務博
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] CD4+ effector T cells specific for irrelevant peptides can induce antitumor reactivity via epitope spreading (2007)
  • Author(s): Kenichi, Koyama, Hirohi, Kagamu, et. al.
  • Organizer: Japanese Cancer Association, annual meeting
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2007-10-03
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] CD4+ effector T cells specific for irrelevant peptides can induce antitumor reactivity via epitope spreading (2007)
  • Author(s): 小山建一、各務博
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] OVA peptide-responsive CD4+effector T cells can induce antitumor immunity via epitope spreading mediated by dendritic cells (2007)
  • Author(s): 小山建一、各務博
  • Organizer: American Association for Cancer Research
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2007-04-16
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] OVA peptide-responsive CD4^+ effector T cells can induce antitumor immunity via epitope spreading mediated by dendritic cells (2007)
  • Author(s): Kenichi, Koyama, Hiroshi, Kagamu, et. al.
  • Organizer: American Association for Cancer Research, annual meeting
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2007-04-16
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] OVA peptide-responsive CD4^+ effector T cells can induce antitumor immunity via epitope spreading mediated by dendritic cells (2007)
  • Author(s): 小山建一、各務博
  • Organizer: American Association for Cancer Research
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2007-04-16