Effect of combination of IL-18 and immune checkpoint inhibitors on peritoneal dissemination of tumor cells

• Project/Area Number: 24390306
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Hyogo Medical University
• Principal Investigator: Okamura Haruki 兵庫医科大学, 医学部, 教授 (60111043)
• Co-Investigator(Kenkyū-buntansha): 笹子 三津留 兵庫医科大学, 医学部, 教授 (40143490) ; 菊池 正二郎 兵庫医科大学, 医学部, 准教授 (70381960) ; 前山 義博 兵庫医科大学, 医学部, 非常勤講師 (80614031) ; 田中 義正 長崎大学, 医歯(薬)学総合研究科, 准教授 (90280700) ; 久保 秀司 兵庫医科大学, 医学部, 准教授 (10441320)
• Research Collaborator: LI Wen ; MA Zhifeng ; Yosif El-Darawish ; SEKI Hatsuka
• Project Period (FY): 2012-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2015: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
• Keywords: IL-18 / 免疫チェックポイント阻害薬 / 抗CTLA4抗体 / 抗PD-L1抗体 / NK細胞 / Treg / CD8陽性T細胞 / 抗CTLA4 抗体 / 抗PD-１抗体 / 抗PD-L１抗体 / IDO阻害剤 / ミトコンドリア / オートファジー / がん免疫治療 / CTLA4 / PD-L1 / CD８陽性T細胞 / CD8陽性細胞 / γδT細胞 / 抗腫瘍効果 / ヘルパーNK細胞 / γδＴ細胞 / γδTリンパ球 / サイトカイン / 胃がん / 腹膜播種 / 微小環境

Outline of Final Research Achievements

This study was carried out on the trial to examine the utility of interleukin-18 (IL-18) for cancer immunotherapy. Recent development of immune checkpoint inhibitors targeting PD-1 or PD-L1 for cancer immunotherapy have made a breakthrough and opened new era in cancer therapy. This therapy requires further progress in augmentation of efficacy and suppression of adverse events. Using an animal model of cancer peritoneal dissemination, we demonstrated that IL-18 markedly augments the efficacy of immune checkpoint inhibitors suppressing tumor growth and prolonging survival of mice inoculated with tumor cells. As a mechanism, it was considered that IL-18 strongly enhances expansion of effector cells including NK cells, γδ T cells, and CD8+ T cells, and oppositely suppresses Treg cells. These results demonstrated utility of IL-18 in cancer immunotherapy and suggested usage of IL-18 for wider range of immunotherapy.

Research Products

• [Journal Article] Dysfunction of mitochondria and deformed gap junctions in the heart of IL-18-deficient mice. (2016)
  • Author(s): Wen Li, Denan Jin, Masaki Hata, Shinji Takai, Kyosuke Yamanishi, Weili Shen, Yosif El-Darawish, Hiromichi Yamanishi, and Haruki Okamura
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 311 Issue: 2 Pages: H313-H325
  • DOI: 10.1152/ajpheart.00927.2015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Augmentation of Immune Checkpoint Cancer Immunotherapy with IL18. (2016)
  • Author(s): Ma Z, Li W, Yoshiya S, Xu Y, Hata M, El-Darawish Y, Markova T, Yamanishi K, Yamanishi H, Tahara H, Tanaka Y, Okamura H.
  • Journal Title: Clin Cancer Res. Volume: 印刷中 Issue: 12 Pages: 2969-2980
  • DOI: 10.1158/1078-0432.ccr-15-1655
  • Open Access / Acknowledgement Compliant
• [Journal Article] Regulation of development of CD56(bright)CD11c(+) NK-like cells with helper function by IL-18. (2013)
  • Author(s): Li W, Okuda A, Yamamoto H, Yamanishi K, Terada N, Yamanishi H, Tanaka Y, Okamura H.
  • Journal Title: PLoS One. Volume: 8 Issue: 12 Pages: e82586-e82586
  • DOI: 10.1371/journal.pone.0082586
  • Peer Reviewed
• [Journal Article] Zoledronic acid-induced expansion of γ δT cells from early-stage breast cancer patients : effect of IL-18 on helper NK cells (2013)
  • Author(s): Sugie, T., Murata-Hirai, K., Iwasaki, M., Morita, C. T., Li, W., Okamura, H., Minato, N., Toi, M., Tanaka, Y.
  • Journal Title: Cancer Immunol. Immunoth Volume: (印刷中) Issue: 4 Pages: 677-87
  • DOI: 10.1007/s00262-012-1368-4
  • Peer Reviewed
• [Journal Article] Changes in Interleukin 18 in the Retinas of Otsuka Long-Evans Tokushima Fatty Rats, a Model of Human Type 2 Diabetes (2013)
  • Author(s): Nagai N, Ito Y, Okamoto N, Shimomura Y, Okamura H.
  • Journal Title: Journal of Oleo Science Volume: 62 Issue: 7 Pages: 513-523
  • DOI: 10.5650/jos.62.513
  • NAID: 130004436070
  • ISSN: 1345-8957, 1347-3352
  • Peer Reviewed
• [Journal Article] Valproic acid cooperates with hydralazine to augment the susceptibility of human osteosarcoma (2012)
  • Author(s): Yamanegi K, Yamane J, Kobayashi K, Kato-Kogoe N, Ohyama H, Nakasho K, YamadaN, Hata M, Fukunaga S, Futani H, Okamura H, Terada N.
  • Journal Title: cells to Fas- and NK cell-mediated cell death.Int J Oncol. Volume: 41(1) Pages: 83-91
  • DOI: 10.3892/ijo.2012.1438
  • Peer Reviewed
• [Journal Article] Cisplati-induced acute renal failure in mice is mediated by chymase-activated angiotensin-aldosterone system and interleukin-18 (2012)
  • Author(s): Shin Okui
  • Journal Title: European Journal of Pharmacology Volume: 685 Issue: 1-3 Pages: 149-155
  • DOI: 10.1016/j.ejphar.2012.04.027
  • Peer Reviewed
• [Journal Article] Hypoxia downregulates the expression of cell surface MICA without increasing soluble MICA in osteosarcoma cells in a HIF-1α-dependent manner. (2012)
  • Author(s): Yamada N, Yamanegi K, Ohyama H, Hata M, Nakasho K, Futani H, Okamura H, Terada N.
  • Journal Title: Int J Oncol. Volume: 41(6) Issue: 6 Pages: 2005-2012
  • DOI: 10.3892/ijo.2012.1630
  • Peer Reviewed
• [Presentation] IL-18 augments efficacy of immunotherapy against peritoneal disseminated tumors in mice (2016)
  • Author(s): Li Wen, Ma Zhifeng, Hata Masaki, Yamanishi Kyosuke, Tanaka Yoshimasa, and Okamura Haruki
  • Organizer: International Congress of Immunology 2016
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] Augmentation of immune checkpoint blockade therapy with IL-18. (2015)
  • Author(s): Ma Z, Li W, Yoshiya S, Xu Y, Hata M, El-Darawish Y, Markova T, Yamanishi K, Yamanishi H, Tahara H, Tanaka Y, Okamura H.
  • Organizer: The 44th Annual Meeting of The Japanese Society for Immunology
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] Augmention of immune checkpoint blockade therapy with IL-18. (2015)
  • Author(s): Ma Z, Li W, Yoshiya S, Xu Y, Hata M, El-Darawish Y, Yamanishi K, Yamanishi H, Tanaka Y, Okamura H.
  • Organizer: The 74th Annual Meeting of The Japanese Cancer Association
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] IL-18 augments efficacy of Immunotherapy against peritoneally disseminated tumor in mice. (2015)
  • Author(s): Li W, Okamura H.
  • Organizer: BIT’s 8th Annual World Cancer Congress
  • Place of Presentation: Beijing, China
  • Year and Date: 2015-05-14
  • Int'l Joint Research
• [Presentation] IL-18 augments efficacy of anti-CTLA4 and /or anti PD-L1 antibodies against peritoneally disseminated tumors in mice. (2014)
  • Author(s): Ma Z, Li W, Hata M, Tanaka Y, Okamura H.
  • Organizer: The 43rd Annual Meeting of The Japanese Society for Immunology
  • Place of Presentation: Kyoto,Japan
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Regulatory roles of novel NK-like CD56brightCD11c+ cells on expansion of gd T cells and memory CD8+ T cells. (2013)
  • Author(s): W Li, H Yamamoto, K Yamanishi, H Yamanishi, Y Tanaka, H Okamura.
  • Organizer: 15th International Congress of Immunology - ICI
  • Place of Presentation: Milan, Italy
• [Presentation] Regulatory roles of CD56brightCD11c+ NK-like cells on expansion of gd T cells. (2013)
  • Author(s): Wen Li, Yoshimasa Tanaka, and Haruki Okamura.
  • Organizer: The 42th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Chiba,Japan
• [Presentation] Regulatory roles of novel NK-like cells on expansion of gdT cells: about plasmacytoid dendritic cells and IL-18 (2012)
  • Author(s): Li W, Yamamoto H, Yamanishi H, etc
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-19
• [Book] Regulation and physiological roles of IL-18.（Cytokine Frontiers: Regulation of Immune Responses in Health and Disease） (2013)
  • Author(s): Li W, Tanaka Y, Okamura H.
  • Total Pages: 21
  • Publisher: Springer
• [Book] 抗ＰＤ－１抗体：基礎と臨床応用 （癌と化学療法 第40巻、9号、特集 免疫療法の新展開） (2013)
  • Author(s): 田中義正、岡村春樹
  • Total Pages: 5
  • Publisher: 癌と化学療法社
• [Book] γδT細胞による治療 (2012)
  • Author(s): 田中義正, 岡村春樹
  • Total Pages: 5
  • Publisher: 日本臨床