Anti-tumor immune responses mediated by TLR-activated tumor-associated myeloid cells

• Project/Area Number: 16K08704
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya City University (2017-2018); Hokkaido University (2016)
• Principal Investigator: Shime Hiroaki 名古屋市立大学, 大学院医学研究科, 講師 (70372133)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 腫瘍免疫 / がん免疫 / 自然免疫 / TLR / TAM / MDSC / 免疫抑制 / アジュバント / 腫瘍内微小環境 / ミエロイド系細胞 / RNAアジュバント / がん免疫療法 / toll-like receptor (TLR) / ミエロイド

Outline of Final Research Achievements

We analyzed the effects of Toll-like receptor (TLR) 2 or TLR3 signals on myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in tumor-bearing mice. TLR3 activation induced cytotoxic activity of MDSCs against cancer cells, leading to tumor growth inhibition. In combination with radiation treatment, TLR3 ligand-stimulated TAMs enhanced the radiosensitivity of cancer cells to potentiate therapeutic effect. In contrast, TLR2 stimulation enhanced the immunosuppressive activity of MDSCs and TAMs, resulted in decreasing therapeutic efficacy. These results suggest that activation of TLR signaling in MDSCs and TAMs has a significant impact on cancer progression.

Academic Significance and Societal Importance of the Research Achievements

がんに対する免疫療法のうち、臨床でも効果が認められている薬剤は、免疫チェックポイント阻害剤に限られる。しかし、全てのがんに有効ではないため、新たな作用機序を持つがん治療薬の開発に向けた基礎研究が必要である。本研究では、腫瘍内の免疫抑制性ミエロイド細胞であるMDSCやTAMの機能制御によるがん治療の可能性を示した。

Research Products

• [Journal Article] Anti-oxidative Amino Acid L-ergothioneine Modulates the Tumor Microenvironment to Facilitate Adjuvant Vaccine Immunotherapy (2019)
  • Author(s): Yoshida Sumito、Shime Hiroaki、Matsumoto Misako、Kasahara Masanori、Seya Tsukasa
  • Journal Title: Frontiers in Immunology Volume: 10
  • DOI: 10.3389/fimmu.2019.00671
  • Peer Reviewed / Open Access
• [Journal Article] Hyperglycemia is associated with psoriatic inflammation in both humans and mice (2019)
  • Author(s): Ikumi K, Odanaka M, Shime H, Imai M, Osaga S, Taguchi O, Nishida E, Hemmi H, Kaisho T, Morita A, Yamazaki S
  • Journal Title: Journal of Investigative Dermatology Volume: 印刷中 Issue: 6 Pages: 1329-1338
  • DOI: 10.1016/j.jid.2019.01.029
  • Peer Reviewed / Open Access
• [Journal Article] Vaccine immunotherapy with ARNAX induces tumor-specific memory T cells and durable anti-tumor immunity in mouse models. (2018)
  • Author(s): Takeda Y, Yoshida S, Takashima K, Ishii‐Mugikura N, Shime H, Seya T, Matsumoto M.
  • Journal Title: Cancer science Volume: 109 Issue: 7 Pages: 2119-2129
  • DOI: 10.1111/cas.13649
  • NAID: 120006502508
  • Peer Reviewed / Open Access
• [Journal Article] TLRアゴニストを用いた抗癌免疫アジュバント療法 (2018)
  • Author(s): 志馬寛明、松本美佐子、山崎小百合、瀬谷 司
  • Journal Title: Thrombosis Medicine Volume: 8(2) Pages: 5-12
• [Journal Article] Type I Interferon-Independent Dendritic Cell Priming and Antitumor T Cell Activation Induced by a Mycoplasma fermentans Lipopeptide (2018)
  • Author(s): Takeda Yohei、Azuma Masahiro、Funami Kenji、Shime Hiroaki、Matsumoto Misako、Seya Tsukasa
  • Journal Title: Frontiers in Immunology Volume: 9
  • DOI: 10.3389/fimmu.2018.00496
  • Peer Reviewed / Open Access
• [Journal Article] Toll-like receptor 3 signal augments radiation-induced tumor growth retardation in a murine model (2018)
  • Author(s): Yoshida Sumito、Shime Hiroaki、Takeda Yohei、Nam Jin-Min、Takashima Ken、Matsumoto Misako、Shirato Hiroki、Kasahara Masanori、Seya Tsukasa
  • Journal Title: Cancer Science Volume: 109 Issue: 4 Pages: 956-965
  • DOI: 10.1111/cas.13543
  • Peer Reviewed / Open Access
• [Journal Article] Ultraviolet B?Induced Maturation of CD11b-Type Langerin?Dendritic Cells Controls the Expansion of Foxp3+Regulatory T Cells in the Skin (2017)
  • Author(s): Yamazaki Sayuri、Odanaka Mizuyu、Nishioka Akiko、Kasuya Saori、Shime Hiroaki、Hemmi Hiroaki、Imai Masaki、Riethmacher Dieter、Kaisho Tsuneyasu、Ohkura Naganari、Sakaguchi Shimon、Morita Akimichi
  • Journal Title: The Journal of Immunology Volume: 200 Issue: 1 Pages: 119-129
  • DOI: 10.4049/jimmunol.1701056
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toll-like receptor 2 ligand and interferon-γ suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cells (2017)
  • Author(s): Shime Hiroaki、Maruyama Akira、Yoshida Sumito、Takeda Yohei、Matsumoto Misako、Seya Tsukasa
  • Journal Title: OncoImmunology Volume: 7 Issue: 1 Pages: e1373231-e1373231
  • DOI: 10.1080/2162402x.2017.1373231
  • NAID: 120006456415
  • Peer Reviewed / Open Access
• [Journal Article] The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc Min/+ mice (2017)
  • Author(s): Ono Junya、Shime Hiroaki、Takaki Hiromi、Takashima Ken、Funami Kenji、Yoshida Sumito、Takeda Yohei、Matsumoto Misako、Kasahara Masanori、Seya Tsukasa
  • Journal Title: Journal of Biomedical Science Volume: 24 Issue: 1 Pages: 79-88
  • DOI: 10.1186/s12929-017-0387-z
  • NAID: 120006370604
  • Peer Reviewed / Open Access
• [Journal Article] Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b+Ly6G+ intratumor myeloid cells through the TICAM-1 signaling pathway. (2017)
  • Author(s): Shime H, Matsumoto M, Seya T.
  • Journal Title: Cell Death & Differentiation Volume: 24 Issue: 3 Pages: 385-396
  • DOI: 10.1038/cdd.2016.131
  • NAID: 120006337763
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The anti-oxidant ergothioneine augments the immunomodulatory function of TLR agonists by direct action on macrophages. (2017)
  • Author(s): Yoshida, S., Shime, H., Funami, K., Takaki, H., Tomiyama, T., Matsumoto, M., Kasahara, M. and Seya, T.
  • Journal Title: PLoS ONE Volume: 12 Issue: 1 Pages: e0169360-e0169360
  • DOI: 10.1371/journal.pone.0169360
  • NAID: 120006219937
  • Peer Reviewed / Open Access
• [Journal Article] STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation (2016)
  • Author(s): Takashima K, Takeda Y, Oshiumi H, Shime H, Okabe M, Ikawa M, Matsumoto M, Seya T.
  • Journal Title: Biochem Biophys Res Commun Volume: 478 Issue: 4 Pages: 1764-1771
  • DOI: 10.1016/j.bbrc.2016.09.021
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Double-stranded RNA analog and type I interferon regulate expression of Trem paired receptors in murine myeloid cells. (2016)
  • Author(s): Kasamatsu, J., Deng, M., Matsumoto, M., Azuma, M., Funami, K., Shime, H., Kasahara, M., Oshiumi, H. and Seya, T.
  • Journal Title: BMC Immunol. Volume: 17 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s12865-016-0147-y
  • NAID: 120005766743
  • Peer Reviewed / Open Access
• [Journal Article] Live imaging of TAK1 activation in Lewis lung carcinoma 3LL cells implanted into syngeneic mice and treated with polyI:C. (2016)
  • Author(s): Takaoka S, Kamioka Y, Takakura K, Baba A, Shime H, Seya T, Matsuda M
  • Journal Title: Cancer Science Volume: Epub ahead of print Issue: 5 Pages: 644-652
  • DOI: 10.1111/cas.12923
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in ApcMin/+ mice (2019)
  • Author(s): Hiroaki Shime, Misako Matsumoto, Sayuri Yamazaki, Tsukasa Seya
  • Organizer: Nagoya Immunology Network in NCU
  • Int'l Joint Research
• [Presentation] TLR2シグナルはミエロイド由来抑制性細胞のがん免疫抑制作用を増強する (2018)
  • Author(s): 志馬寛明、松本美佐子、山崎小百合、瀬谷司
  • Organizer: 第28回日本樹状細胞研究会
• [Presentation] The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in ApcMin/+ mice (2018)
  • Author(s): Hiroaki Shime, Misako Matsumoto, Sayuri Yamazaki, Tsukasa Seya
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] トル様受容体3リガンドは放射線の増感性免疫アジュバントとして機能する (2018)
  • Author(s): 吉田純人、志馬寛明、武田洋平、松本美佐子、瀬谷司
  • Organizer: 第22回日本がん免疫学会総会
• [Presentation] Toll-like receptor 2 ligand and interferon-γ suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cell. (2017)
  • Author(s): Hiroaki Shime, Misako Matsumoto, Tsukasa Seya
  • Organizer: 日本免疫学会
• [Presentation] Double-stranded RNA induces CTL-independent tumor cytolysis mediated by CD11b+Ly6G+ intratumor myeloid cells through the TICAM-1 signaling pathway (2017)
  • Author(s): Hiroaki Shime, Misako Matsumoto, Tsukasa Seya
  • Organizer: The 36th Sapporo international cancer symposium
  • Int'l Joint Research
• [Presentation] TLR3 adjuvant enhances tumor regression in concert with radiation therapy in mouse tumor-implant models. (2017)
  • Author(s): Sumito Yoshida, Hiroaki Shime, Misako Matsumoto, Masanori Kasahara, Tsukasa Seya
  • Organizer: The 36th Sapporo international cancer symposium
  • Int'l Joint Research
• [Presentation] PolyI:C-induced, TLR3/RIP3-dependent necroptosis backs up immune effector-mediated tumor elimination in vivo. (2017)
  • Author(s): Hiromi Takaki, Hiroaki Shime, Misako Matsumoto, Tsukasa Seya
  • Organizer: The 36th Sapporo international cancer symposium
  • Int'l Joint Research
• [Presentation] STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation. (2017)
  • Author(s): Ken Takashima, Yohei Takeda, Hiroyuki Oshiumi, Hiroaki Shime, Misako Matsumoto, Tsukasa Seya
  • Organizer: The 36th Sapporo international cancer symposium
  • Int'l Joint Research
• [Presentation] ApcMin/+マウスでのTICAM-1遺伝子欠損は腸ポリープ形成を促進する (2016)
  • Author(s): 尾野 純也、志馬 寛明、松本 美佐子、瀬谷 司
  • Organizer: 日本分子生物学会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-11-30
• [Presentation] T cell-derived IFN-γ is a critical factor for enhanced suppressive activity of M-MDSCs induced by TLR2 activation (2016)
  • Author(s): Hiroaki Shime, Akira Maruyama, Misako Matsumoto, Tsukasa Seya
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-06
• [Presentation] TLRシグナルの活性化による腫瘍内ミエロイド系免疫細胞の機能変化と腫瘍退縮機構 (2016)
  • Author(s): 志馬寛明、松本美佐子、瀬谷 司
  • Organizer: 日本インターフェロンサイトカイン学会
  • Place of Presentation: 長崎大学坂本キャンパス良順会館 ポンペ会館（長崎県・長崎市）
  • Year and Date: 2016-05-13