Study for mechanism of STING-mediated inflammation in tumor microenvironment

• Project/Area Number: 16K19070
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Asahikawa Medical College
• Principal Investigator: Ohkuri Takayuki 旭川医科大学, 医学部, 講師 (70564061)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: STING / macrophages / マクロファージ / I型IFN / 腫瘍免疫

Outline of Final Research Achievements

STING contributes to anti-tumor immunity through sensing tumor-derived genomic DNAs in the tumor-bearing host. Although injection of STING ligands into tumor sites shows anti-tumor effects via inducing type I IFNs and activating immune system, precise events caused in the tumor remain to be assessed. We found that CD11b+ Ly6C+ cells were found to robustly accumulate into the tumor site after intratumoral injection of STING ligand, cGAMP in the 4T1 mouse model. The accumulating subsets were positive for F4/80 and Ly6C but not Ly6G, macrophage phenotypes. The accumulating macrophages in the tumor site were also confirmed in the other mouse models. In STING-deficient mice, intratumoral cGAMP treatment did not induce macrophage accumulation. The functional analyses revealed that the macrophages showed activities of phagocytosis and TNFa production. These results demonstrate that the accumulating macrophages into the tumor site by STING stimulation contribute to the anti-tumor immunity.

Research Products

• [Journal Article] Effects of STING stimulation on macrophages: STING agonists polarize into "classically" or "alternatively" activated macrophages? (2018)
  • Author(s): Ohkuri T, Kosaka A, Nagato T, Kobayashi H.
  • Journal Title: Hum Vaccin Immunother Volume: 14(2) Issue: 2 Pages: 285-287
  • DOI: 10.1080/21645515.2017.1395995
  • Peer Reviewed / Open Access
• [Journal Article] Intratumoral injection of IFN-β induces chemokine production in melanoma and augments the therapeutic efficacy of anti-PD-L1 mAb. (2017)
  • Author(s): Uehara J, Ohkuri T, Kosaka A, Ishibashi K, Hirata Y, Ohara K, Nagato T, Oikawa K, Aoki N, Harabuchi Y, Ishida-Yamamoto A, Kobayashi H.
  • Journal Title: Biochem Biophys Res Commun Volume: 490(2) Issue: 2 Pages: 521-527
  • DOI: 10.1016/j.bbrc.2017.06.072
  • Peer Reviewed / Open Access
• [Journal Article] Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site. (2017)
  • Author(s): Ohkuri T, Kosaka A, Ishibashi K, Kumai T, Hirata Y, Ohara K, Nagato T, Oikawa K, Aoki N, Harabuchi Y, Celis E, Kobayashi H.
  • Journal Title: Cancer Immunology, Immunotherapy Volume: - Issue: 6 Pages: 705-716
  • DOI: 10.1007/s00262-017-1975-1
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] STING-mediated inflammation in tumor site (2017)
  • Author(s): 大栗敬幸
  • Organizer: Oncology Focus Symposium in Sapporo
  • Int'l Joint Research / Invited
• [Presentation] Intratumoral STING stimulation recruits M1 macrophage in the tumor via NF-kB/TLR4 pathway to trigger anti!tumor immunity (2017)
  • Author(s): 大栗敬幸
  • Organizer: 第21回がん免疫学会
• [Presentation] Intratumoral cGAMP injection recruits M1 macrophage in the tumor microenvironment via NF-kB/TLR4 pathway to trigger anti-tumor immunity (2017)
  • Author(s): 大栗敬幸
  • Organizer: The 36th Sapporo International Cancer Symposium
  • Int'l Joint Research