The detrimental effect of soluble IL-6 receptor on CD4 T cell-mediated anti-tumor immune responses

• Project/Area Number: 26430165
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Kumamoto University
• Principal Investigator: Tsukamoto Hirotake 熊本大学, 大学院生命科学研究部(医), 助教 (10433020)
• Research Collaborator: Fujieda Koji 熊本大学, 生命科学研究部, リサーチアシスタント ; Ikeda Tokunori 熊本大学, 医学部付属病院, 病院職員 (00613530) ; Nakayama Hideki 熊本大学, 生命科学研究部, 教授 (70381001) ; Araki Kimi 熊本大学, 生命資源研究・支援センター, 教授 (90211705) ; Senju Satoru 熊本大学, 生命科学研究部, 准教授 (50274709) ; Nishimura Yasuharu 熊本大学, 生命科学研究部, 教授 (10156119)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 抗腫瘍免疫応答 / 炎症 / T細胞 / IL-6 / 免疫抑制 / がん免疫療法 / sIL-6R / 抗腫瘍免疫 / 癌免疫療法 / CD4陽性T細胞 / 可溶性IL-6受容体 / Th1分化

Outline of Final Research Achievements

It is well known that pro-inflammatory cytokine IL-6 produced by tumor cells promotes their own survival, therefore is a poor prognostic factor in cancer patients. In terms of anti-tumor immune responses, Th1 differentiation of tumor-specific CD4 T cells is attenuated in tumor-bearing animals in an IL-6-dependent fashion. In this study, we investigated the immune-suppressive effects of IL-6 signaling by focusing on IL-6 trans-signaling mediated thorough a soluble form of IL-6 receptor (sIL-6R).
We found that accompanied by the systemic increase of sIL-6R in cancer patients, blunted activity of sIL-6R restored the Th1 responses, their helper activity toward CD8 T cells, and anti-tumor activity in tumor-bearing mice. Our findings suggest the implication of the increase in IL-6 signaling as an adverse event counteracting tumor-specific Th1 generation, and that sIL-6R is considered for a rational target to improve the effectiveness of T cell-mediated cancer immunotherapy.

Research Products

• [Int'l Joint Research] Univ. Massachusetts Medical School(米国)
• [Journal Article] Soluble IL-6R expressed by myeloid cells Th1 differentiation and drives tumor progression. (2017)
  • Author(s): Tsukamoto H., Fujieda K., Hirayama M., Ikeda T., Yuno A., Matsumura K., Fukuma D, Araki K., Hiroshi M., Nakayama H., Senju S. and Nishimura Y.
  • Journal Title: Cancer Research Volume: 印刷中
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Extracellular vesicles deliver host and virus RNA and regulate innate immune response. (2017)
  • Author(s): Kouwaki T., Okamoto M., Tsukamoto H., Fukushima Y. and Oshiumi H.
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 3 Pages: 666-666
  • DOI: 10.3390/ijms18030666
  • Peer Reviewed / Open Access
• [Journal Article] An oncofetal antigen, IMP-3-derived long peptides induce immune responses of both helper T cells and CTLs. (2016)
  • Author(s): Hirayama M., Tomita Y., Yuno A., Tsukamoto H., Senju S., Imamura Y., Sayem M., Irie A., Yoshitake Y., Fukuma D., Shinohara M., Hamada A., Jono H., Yuba E., Kono K., Yoshida K., Tsunoda T., Nakayama H., and Nishimura Y.
  • Journal Title: Oncoimmunology Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Glypican-3-derived long peptides activating both CD8+ and CD4+ T-cells; prolonged overall survival in cancer patients with Th cell response. (2016)
  • Author(s): 2.Sayem M., Tomita Y., Yuno A., Hirayama M., Irie A., Tsukamoto H., Senju S., Yuba E., Yoshikawa T., Kono K., Nakatsura T., and Nishimura Y.
  • Journal Title: Oncoimmunology Volume: 5
  • Peer Reviewed / Open Access
• [Journal Article] IL-6-mediated environmental conditioning of defective Th1 differentiation dampens anti-tumor immune responses in old age. (2015)
  • Author(s): Tsukamoto, H., Senju, S., Matsumura, K., Swain, S.L., and Nishimura, Y.
  • Journal Title: Nature Communications Volume: 6 Issue: 1 Pages: 6702-6702
  • DOI: 10.1038/ncomms7702
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CXCL10 and CCL2 mRNA expression in monocytes is inversely correlated with the HLA-DR lower fraction of monocytes in patients with renal cell carcinoma. (2015)
  • Author(s): 4.Motoshima T., Komohara Y., Horlad H., Tsukamoto H., Fujita M., Saito Y., Tanoue K., Kasejima Y., Sugiyama Y., Kawano Y., Nishimura Y., Takeya M., Eto M.
  • Journal Title: Oncol Lett Volume: ２ Pages: 4132-4132
  • Peer Reviewed
• [Journal Article] CXCL10 and CCL2 mRNA expression in monocytes is inversely correlated with the HLA-DR lower fraction of monocytes in patients with renal cell carcinoma. (2015)
  • Author(s): Motoshima T., Komohara Y., Horlad H., Tsukamoto H., Fujita M., Saito Y., Tanoue K., Kasejima Y., Sugiyama Y., Kawano Y., Nishimura Y., Takeya M., Eto M.
  • Journal Title: Oncology letters Volume: In Press
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of Th1-mediated autoimmunity by embryonic stem cell-derived dendritic cells. (2014)
  • Author(s): 13.Suppression of Th1-mediated autoimmunity by embryonic stem cell-derived dendritic cells.da, T., Hirata, S., Takamatsu, K., Haruta, M., Tsukamoto, H., Ito, T., Uchino, M., Ando, Y., Nagafuchi, S., Nishimura, Y., Senju, S.
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e115198-e115198
  • DOI: 10.1371/journal.pone.0115198
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LY6K-specific CD4+ T-cell immunity in patients with malignant tumor: Identification of LY6K long peptide encompassing both CD4+ and CD8+ T-cell epitopes. (2014)
  • Author(s): Tomita Y., Yuno A., Tsukamoto H., Senju S., Kuroda Y., Hirayama M. Irie A., Yatsuda J., Hamada A., Jono H., Yoshida K., Tsunoda T., Daigo Y., Kohrogi H., Yoshitake Y., Nakamura Y., Shinohara M., and Nishimura Y.
  • Journal Title: Oncoimmunology Volume: 3
  • Peer Reviewed / Open Access
• [Journal Article] Identification of CDCA1 long peptides bearing both CD4+ and CD8+ T-cell epitopes: CDCA1-specific CD4+ T-cell immunity in cancer patients. (2014)
  • Author(s): Tomita Y., Yuno A., Tsukamoto H., Senju S., Yoshimura S., Osawa R., Kuroda Y., Hirayama M., Hamada A., Jono H., Irie A., Tsunoda T., Kohrogi H., Yoshitake Y., Nakamura Y., Shinohara M., and Nishimura Y.
  • Journal Title: International Journal of Cancer Volume: 134 Pages: 352-366
  • Peer Reviewed / Open Access
• [Presentation] SASP factor IL-6-mediated dysfunction of CD4 T cells diminishes anti-tumor immunity in old age (2016)
  • Author(s): 塚本博丈
  • Organizer: 日本分子生物学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-08
  • Invited
• [Presentation] Immune-suppressive role of IL-6/sIL-6R signaling in CD4 T cell-mediated anti-tumor immunity (2016)
  • Author(s): 塚本博丈
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-08
  • Invited
• [Presentation] IL-6/可溶性IL-6受容体を介したT細胞抗腫瘍免疫応答の抑制機構 (2016)
  • Author(s): 塚本博丈
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06
  • Invited
• [Presentation] 癌患者で上昇する可溶性IL-6受容体(soluble IL-6; sIL-6R)がTh1細胞の分化に及ぼす影響の検討 (2016)
  • Author(s): 藤枝浩司
  • Organizer: 日本がん免疫学会
  • Place of Presentation: 大阪国際交流センター
  • Year and Date: 2016-07-28
• [Presentation] sIL-6R-mediated defective Th1 differentiation dampens anti-tumor immune responses in tumor-bearing mice. (2015)
  • Author(s): Hirotake Tsukamoto, Satoru Senju, Yasuharu Nishimura
  • Organizer: 免疫学会学術総会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] Multifaceted dysfunction of CD4 T cells during aging process and their impact on antitumor immunity (2015)
  • Author(s): Hirotake Tsukamoto, Satoru Senju, Keiko Matsumura, Susan Swain, Yasuharu Nishimura
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 名古屋コングレスセンター
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] IL-6-mediated c-Maf induction attenuates Th1 differentiation and anti-tumor immune responses in old age. (2015)
  • Author(s): Hirotake Tsukamoto, Satoru Senju, Keiko Matsumura, Susan L Swain, Yasuharu Nishimura
  • Organizer: 日本がん免疫学会総会・マクロファージ分子細胞生物学国際シンポジウム
  • Place of Presentation: 東京大学 伊藤国際学術センター 伊藤謝恩ホール
  • Year and Date: 2015-07-09
  • Int'l Joint Research
• [Presentation] IL-6-mediated environmental conditioning of defective Th1 differentiation dampens anti-tumour immune responses in old age. (2014)
  • Author(s): Hirotake Tsukamoto, Satoru Senju, Susan L. Swain, Yasuharu Nishimura
  • Organizer: 第43回日本免疫学会総会・学術集会
  • Place of Presentation: 京都国際会議場（京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 老齢個体で増加するIL-6は、CD4+T細胞を介した抗腫瘍免疫応答を抑制する (2014)
  • Author(s): 塚本 博丈、 千住 覚、 松村 桂子、 Susan L. Swain、 西村 泰治
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめぎんホール（愛媛県松山市）
  • Year and Date: 2014-07-30 – 2014-08-01
• [Book] アンチ・エイジング医学 「免疫老化とがん免疫」 (2017)
  • Author(s): 塚本博丈
  • Publisher: メディカルレビュー社
• [Book] 臨床免疫・アレルギー科 「IL-6と老年における免疫応答の低下」 (2016)
  • Author(s): 塚本博丈
  • Total Pages: 7
  • Publisher: 科学評論社
• [Book] 臨床免疫・アレルギー科 (2016)
  • Author(s): 塚本博丈
  • Total Pages: 8
  • Publisher: 科学評論社
• [Book] 臨床免疫・アレルギー科 「Myeloid-derived suppressor cells (MDSC)によるTh1細胞の抑制機序」 (2014)
  • Author(s): 塚本博丈
  • Total Pages: 8
  • Publisher: 科学評論社