Development of novel treatment to target immune suppressive cells in tumor microenvironment

• Project/Area Number: 17K16892
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Otorhinolaryngology
• Research Institution: Chiba University
• Principal Investigator: Ihara Fumie 千葉大学, 大学院医学研究院, 助教 (40779906)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 制御性T細胞 / 頭頸部扁平上皮癌 / 骨髄性抑制細胞 / effector Treg / NKT細胞 / 免疫学 / Treg / MDSC / 腫瘍浸潤細胞

Outline of Final Research Achievements

Regulatory T cells (Treg) reportedly play a crucial role in suppressing anti-tumor immunity in advanced cancer patients. We demonstrated increased numbers of activated Tregs in the peripheral blood of head and neck cancer (HNC) patients and confirmed that Tregs exerted a potent suppressive effect on other immune cells. Thus, we aimed to detect activated Treg-specific genes as a diagnostic biomarker for recurrence or metastasis of HNC and evaluate the utility of paclitaxel (PTX) in selectively suppressing the Treg function.
We identified several candidate genes whose expression was specific for Tregs derived from advanced HNC patients. Low-dose PTX suppressed Treg proliferation and the cytokine function, but not in cytotoxic T cells. The suppressive effects of PTX on Tregs could lead to the restoration of other immune cell functions, such as the cytotoxic activity of NKT cells. Our results suggest the possible utility of Treg-targeted therapy as a therapeutic strategy for advanced HNC.

Academic Significance and Societal Importance of the Research Achievements

頭頸部癌患者では、増加した活性型Tregにより臨床経過が不良となることから、パクリタキセルや、活性型Tregに特異的な遺伝子や表面抗原などを標的とした新規治療の開発は、Tregの抑制効果を減弱させ、担癌患者における免疫抑制の解除につながることから、今後の頭頸部癌患者の新たな治療戦略の確立という点において非常に有意義と考える。

Research Products

• [Journal Article] Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation (2019)
  • Author(s): Harada, K., Ihara, F., Takami, M., Kamata, T., Mise, N., Yoshizawa, H., Hishiki, T., Saito, T., Terui, K., Nakata, M., Komatsu, S., Ikeuchi, T., Nakayama, T., Yoshida, H., Motohashi, S.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 3 Pages: 888-902
  • DOI: 10.1111/cas.13933
  • Peer Reviewed / Open Access
• [Journal Article] Immunosuppressive property of submandibular lymph nodes in patients with head and neck tumors: differential distribution of regulatory T cells (2018)
  • Author(s): Sakurai D, Uchida R, Ihara F, Kunii N, Nakagawa T, Chazono H, Hanazawa T, Motohashi S, Okamoto Y
  • Journal Title: BMC Research Notes Volume: 11 Issue: 1 Pages: 479-479
  • DOI: 10.1186/s13104-018-3587-z
  • Peer Reviewed / Open Access
• [Journal Article] Activated iNKT cells enhance the anti-tumor effect of antigen specific CD8 T cells on mesothelin-expressing salivary gland cancer (2018)
  • Author(s): Makita Yuji、Kunii Naoki、Sakurai Daiju、Ihara Fumie、Motohashi Shinichiro、Suzuki Akane、Nakayama Toshinori、Okamoto Yoshitaka
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 1254-1254
  • DOI: 10.1186/s12885-018-5179-7
  • Peer Reviewed / Open Access
• [Journal Article] Frequency and proliferative response of circulating invariant natural killer T cells in pediatric patients with or without malignant solid tumors. (2018)
  • Author(s): Hishiki T, Mise N, Harada K, Ihara F, Takami M, Saito T, Terui K, Nakata M, Komatsu S, Yoshida H, and Motohashi S
  • Journal Title: Pediatr. Surg. Int. Volume: 34 Issue: 2 Pages: 169-176
  • DOI: 10.1007/s00383-017-4185-1
  • Peer Reviewed
• [Journal Article] Invariant natural killer T infiltration in neuroblastoma with favorable outcome. (2018)
  • Author(s): Hishiki T, Mise N, Harada K, Ihara F, Takami M, Saito T, Terui K, Nakata M, Komatsu S, Yoshida H, and Motohashi S
  • Journal Title: Pediatr. Surg. Int. Volume: 34 Issue: 2 Pages: 195-201
  • DOI: 10.1007/s00383-017-4189-x
  • Peer Reviewed
• [Journal Article] CD45RA-Foxp3high regulatory T cells have a negative impact on the clinical outcome of head and neck squamous cell carcinoma (2017)
  • Author(s): Ihara Fumie、Sakurai Daiju、Horinaka Atsushi、Makita Yuji、Fujikawa Akira、Sakurai Toshioki、Yamasaki Kazuki、Kunii Naoki、Motohashi Shinichiro、Nakayama Toshinori、Okamoto Yoshitaka
  • Journal Title: Cancer Immunol Immunother. Volume: 66 Issue: 10 Pages: 1275-1285
  • DOI: 10.1007/s00262-017-2021-z
  • Peer Reviewed / Open Access
• [Presentation] メソテリン特異的CART細胞と活性化NKT細胞を併用したがん免疫細胞療法の有効性に関する前臨床研究 (2019)
  • Author(s): 國井直樹、 伊原史英、 松島可奈、 飯沼智久、米倉修二、 茶薗英明、 櫻井大樹、 花澤豊行、 岡本美孝
  • Organizer: 第37回日本耳鼻咽喉科免疫アレルギー学会
• [Presentation] 頭頸部癌患者の免疫抑制と免疫細胞療法による治療戦略 (2019)
  • Author(s): 伊原史英、櫻井大樹、 飯沼智久、國井直樹、米倉修二、 岡本美孝
  • Organizer: 第37回日本耳鼻咽喉科免疫アレルギー学会
• [Presentation] A role for immune checkpoint inhibitors in iNKT cell-based immunotherapy. (2018)
  • Author(s): Negawa M, Ihara F, Kamata T, Takami M, Motohashi S.
  • Organizer: The 2nd Chiba University - UC San Diego Symposium
  • Int'l Joint Research
• [Presentation] 頭頸部扁平上皮癌患者における制御性T細胞の臨床的意義 (2018)
  • Author(s): 伊原史英、 高見真理子、 國井直樹、 櫻井大樹、 岡本美孝、 本橋新一郎
  • Organizer: 第22回日本がん免疫学会総会
• [Presentation] A Phase II study of α-Galactosylceramide-pulsed antigen presenting cells for advanced or recurrent non-small cell lung cancer (2018)
  • Author(s): Motohashi S, Kamata T, Toyoda, T, Tanaka T, Ihara F, Takami M, Yosino I, Nakayama,T
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] 制御性T細胞が頭頸部癌患者に及ぼす免疫抑制作用からの克服を目指した治療法の検討 (2018)
  • Author(s): 伊原史英、櫻井大樹、米倉修二、飯沼智久、岡本美孝
  • Organizer: 第36回日本耳鼻咽喉科免疫アレルギー学会
• [Presentation] 頭頸部扁平上皮癌患者における末梢血制御性T細胞の臨床的意義 (2017)
  • Author(s): 伊原史英、櫻井大樹、堀中敦史、國井直樹、本橋新一郎、岡本美孝
  • Organizer: 第21回日本がん免疫学会
• [Presentation] Regulatory T cells increased in advanced head and neck cancer patients suppress NKT cell function and correlate with disease progression. (2017)
  • Author(s): Ihara, F., Sakura, D., Takami, M., Okamoto, Y., Motohashi, S.
  • Organizer: CD1-MR1 2017
  • Int'l Joint Research
• [Presentation] A role of AhR signaling in NKT cell immunotherapy. (2017)
  • Author(s): Takami, M., Ihara, F., Kamata, T., Motohashi, S.
  • Organizer: CD1-MR1 2017
  • Int'l Joint Research