Studies of neuropeptide signaling on functional regulation of dendritic cells and the pathogenesis of cancer and inflammatory diseases

• Project/Area Number: 15K08416
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Hokkaido University
• Principal Investigator: Kitamura Hidemitsu 北海道大学, 遺伝子病制御研究所, 准教授 (40360531)
• Co-Investigator(Renkei-kenkyūsha): KOBAYASHI Hiroya 旭川医科大学, 医学部, 教授 (90280867) ; OHKURI Takayuki 旭川医科大学, 医学部, 講師 (70564061)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 樹状細胞 / 神経ペプチド / 神経ペプチド受容体 / サイトカイン産生 / 抗原提示能 / 抗原特異的T細胞 / 感染症 / がん

Outline of Final Research Achievements

In this study, we investigated the precise roles of neuropeptide signaling through NK2R, a receptor of neurokinin A, in tumorigenesis of cancer cells and inflammatory bowel disease (IBD) involving with inflammation and immune responses. We found that NK2R expression levels of murine and human dendritic cells were augmented by type-1 IFN stimulations in a STAT-1-dependent manner. Antigen-specific T cell responses were attenuated in the presence of a NK2R antagonist in vitro. Next, we revealed that in vivo administration of a NK2R antagonist reduced tumorigenesis of CT26 cancer cells and disease state of dextran sulfate sodium (DSS)-induced colitis model. Furthermore, we confirmed that NK2R was expressed in lesion and inflammation areas of patients with hepatocellular carcinoma, cervical cancer, colorectal cancers, and IBD. Based on these findings we speculate that regulation of neuropeptide signaling may be a promising tool in the development of effective therapy for cancers and IBD.

Research Products

• [Journal Article] IL-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy (2017)
  • Author(s): Kitamura H, Ohno Y, Toyoshima Y, Ohtake J, Homma S, Kawamura H, Takahashi N, Taketomi A
  • Journal Title: Cancer Science Volume: 108 Issue: 10 Pages: 1947-1952
  • DOI: 10.1111/cas.13332
  • Peer Reviewed / Open Access
• [Journal Article] Lack of IL-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy. (2017)
  • Author(s): Ohno Y, Toyoshima Y, Yurino H, Monma N, Xiang H, Sumida K, Kaneumi S, Terada S, Hashimoto S, Ikeo K, Homma S, Kawamura H, Takahashi N, Taketomi A, Kitamura H
  • Journal Title: Cancer Science Volume: 108 Issue: 10 Pages: 1959-1966
  • DOI: 10.1111/cas.13330
  • Peer Reviewed / Open Access
• [Journal Article] 血清マイクロRNAによる免疫体質判定法の確立とコンパニオン診断薬への応用 (2016)
  • Author(s): 北村秀光
  • Journal Title: 化学工業 Volume: 67 Pages: 27-33
  • Acknowledgement Compliant
• [Journal Article] IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells. (2016)
  • Author(s): Ohno Y, Kitamura H, Takahashi N, Ohtake J, Kaneumi S, Sumida K, Homma S, Kawamura H, Minagawa N, Shibasaki S, Taketomi A.
  • Journal Title: Cancer Immunol Immunother Volume: 65 Issue: 2 Pages: 193-204
  • DOI: 10.1007/s00262-015-1791-4
  • NAID: 120006581487
  • Peer Reviewed
• [Journal Article] Neuropeptide signaling through neurokinin-1 and 2 receptors augments antigen presentation by human dendritic cells. (2015)
  • Author(s): Junya Ohtake, Shun Kaneumi, Mishie Tanino, Takuto Kishikawa, Satoshi Terada, Kentaro Sumida, Kazutaka Masuko, Yosuke Ohno, Toshiyuki Kita, Sadahiro Iwabuchi, Toshiya Shinohara, Yoshinori Tanino, Tamiko Takemura, Shinya Tanaka, Hiroya Kobayashi, and Hidemitsu Kitamura.
  • Journal Title: Journal of Allergy and Clinical Immunology. Volume: 136 Issue: 6 Pages: 1690-1694
  • DOI: 10.1016/j.jaci.2015.06.050
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IL-11 induces differentiation of myeloid-derived suppressor cells through activation of STAT3 signalling pathway. (2015)
  • Author(s): Sumida K, Ohno Y, Ohtake J, Kaneumi S, Kishikawa T, Takahashi N, Taketomi A, Kitamura H.
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 13650-13650
  • DOI: 10.1038/srep13650
  • NAID: 120006365350
  • Peer Reviewed / Open Access
• [Presentation] 炎症性腸疾患におけるSTAT1の活性化を介したシグナルカスケードの関与 (2018)
  • Author(s): 木井修平、北村秀光、項慧慧、橋本真一、池尾一穂、豊島雄二郎、岡田尚樹、大野陽介、市川伸樹、吉田雅、 本間重紀、川村秀樹、高橋典彦、武冨紹信
  • Organizer: 第118回 日本外科学会定期学術集会
• [Presentation] 炎症性腸疾患におけるSTAT1の活性化を介したシグナルカスケードの関与 (2017)
  • Author(s): 木井修平、北村秀光、豊島雄二郎、岡田尚樹、項慧慧、寺田聖、本間重紀、川村秀樹、高橋典彦、武冨紹信
  • Organizer: 第117回 日本外科学会定期学術集会
• [Presentation] Neuropeptide signaling through NK2R is related to tumorigenesis in vivo (2017)
  • Author(s): Huihui Xiang, Yujiro Toyoshima, Satoshi Terada, Shinichi Hashimoto, Kazuho Ikeo, Hiroya Kobayashi, Shigenori Homma, Hideki Kawamura, Norihiko Takahashi, Akinobu Taketomi, Hidemitsu Kitamura
  • Organizer: The 36th Sapporo International Cancer Symposium
  • Int'l Joint Research
• [Presentation] 神経ペプチド受容体を介した腫瘍形成メカニズムの解明と新規がん治療法への応用 (2017)
  • Author(s): 北村秀光、項慧慧、豊島雄二郎、木井修平、橋本真一、池尾一穂、小林博也、本間重紀、川村秀樹、高橋典彦、武冨紹信
  • Organizer: 第21回 日本がん免疫学会総会
• [Presentation] 炎症性腸疾患におけるSTAT1の関与 (2017)
  • Author(s): 木井修平、北村秀光、豊島雄二郎、岡田尚樹、項慧慧、寺田聖、大野陽介、市川伸樹、吉田雅、本間重紀、川村秀樹、高橋典彦、武冨紹信
  • Organizer: 第72回日本大腸肛門病学会学術集会
• [Presentation] Neuropeptide signaling through NK1R and NK2R is related to inflammation and tumorigenesis in vivo (2016)
  • Author(s): Huihui Xiang, Yujiro Toyoshima, Satoshi Terada, Shigenori Homma, Hideki Kawamura, Norihiko Takahashi, Akinobu Taketomi, Hiroya Kobayashi, Hidemitsu Kitamura
  • Organizer: 第45回 日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター、ラグナガーデンホテル（沖縄県・宜野湾市）
  • Year and Date: 2016-12-05
• [Presentation] Neuropeptide signaling through NK1R and NK2R of cancer cells is required for promotion of tumorigenesis in vivo (2016)
  • Author(s): Huihui Xiang, Yujiro Toyoshima, Satoshi Terada, Shigenori Homma, Hideki Kawamura, Norihiko Takahashi, Akinobu Taketomi, Hiroya Kobayashi, Hidemitsu Kitamura
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 血清マイクロRNAによる抗腫瘍免疫応答の判定と個別化がん免疫治療への応用 (2016)
  • Author(s): 北村 秀光, 大竹 淳矢, 寺田 聖, 項慧慧, 豊島雄二郎, 岡田尚樹, 木井修平, 大野 陽介, 本間重紀, 川村秀樹, 高橋典彦, 武冨紹信
  • Organizer: 第8回 血液疾患免疫療法学会
  • Place of Presentation: 北海道大学医学部学友会館「フラテ」（北海道・札幌市）
  • Year and Date: 2016-09-03
• [Presentation] 神経ペプチドシグナルによる腫瘍形成促進メカニズムの解明と新規がん治療法への応用 (2016)
  • Author(s): 項慧慧, 豊島雄二郎, 寺田聖, 本間重紀, 川村秀樹, 高橋典彦, 武冨紹信, 小林博也, 北村秀光
  • Organizer: 第20回 日本がん免疫学会総会
  • Place of Presentation: 大阪国際交流センター（大阪府・大阪市）
  • Year and Date: 2016-07-27
• [Presentation] Neuropeptide signalings enhance cytokine production by antigen-specific T cells through activation of human dendritic cells (2015)
  • Author(s): Hidemitsu Kitamura, Junya Ohtake, Shun Kaneumi, Mishie Tanino, Takuto Kishikawa, Satoshi Terada, Kentaro Sumida, Kazutaka Masuko, Toshiyuki Kita, Sadahiro Iwabuchi, Shinya Tanaka, Hiroya Kobayashi
  • Organizer: 第44回 日本免疫学会学術総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2015-11-18
• [Presentation] NK2R-mediated neuropeptide signaling regulates inflammation and Type-1 immune responses (2015)
  • Author(s): Satoshi Terada, Hidemitsu Kitamura
  • Organizer: 第44回 日本免疫学会学術総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2015-11-18
• [Presentation] A novel mechanism for activating Type-1 immunity by neuropeptide signalings through NK1R and NK2R in tumor microenvironments (2015)
  • Author(s): Takayuki Ohkuri, Junya Ohtake, Shun Kaneumi, Hidemitsu Kitamura, Hiroya Kobayashi
  • Organizer: The 10th International Symposium of the Institute Network “Towards the next generation research for cancer and immunology”
  • Place of Presentation: 北海道大学医学部学友会館「フラテ」（北海道・札幌市）
  • Year and Date: 2015-07-23
  • Int'l Joint Research
• [Book] 臨床免疫・アレルギー科 (2016)
  • Author(s): 大竹淳矢, 寺田聖, 北村秀光
  • Total Pages: 5
  • Publisher: 科学評論社
• [Remarks] ヒト免疫抑制細胞の新しい分化・誘導メカニズムが明らかに
  • URL: http://www.hokudai.ac.jp/news/151007_igm_pr.pdf
• [Remarks] Research Press Release
  • URL: https://www.oia.hokudai.ac.jp/blog/121novel-regulatory-mechanism-to-modulate-human-immune-responses-mediated-by-neuropeptide-receptors/
• [Remarks] ヒト免疫応答を調節する神経ペプチド受容体を介した新たな制御メカニズムの解明
  • URL: http://www.igm.hokudai.ac.jp/public/20150912.html