title: Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site.
abstract: Stimulator of IFN genes (STING) spontaneously contributes to anti-tumor immunity by inducing type I interferons (IFNs) following sensing of tumor-derived genomic DNAs in the tumor-bearing host. Although direct injection of STING ligands such as cyclic diguanylate monophosphate (c-di-GMP) and cyclic [G(2',5')pA(3',5')p] (cGAMP) into the tumor microenvironment exerts anti-tumor effects through strong induction of type I IFNs and activation of innate and adaptive immunity, the precise events caused by STING in the tumor microenvironment remain to be elucidated. We describe here our finding that a CD45+CD11bmidLy6C+cell subset transiently accumulated in mouse tumor microenvironment of 4T1 breast cancer, squamous cell carcinomas, CT26 colon cancer, or B16F10 melanoma tissue after intratumoral injection of cGAMP. The accumulated cells displayed a macrophage (M ) phenotype since the cells were positive for F4/80 and MHC class II and negative for Ly6G. Intratumoral cGAMP treatment did not induce Mφ accumulation in STING-deficient mice. Depletion of CD8+T cell using anti-CD8 mAb impaired the anti-tumor effects of cGAMP treatment. Depletion of the Mφ using clodronate liposomes impaired the anti-tumor effects of cGAMP treatment. Functional analysis indicated that the STING-triggered tumor-migrating Mφ exhibited phagocytic activity, production of tumor necrosis factor alpha TNFα), and high expression levels of T cell-recruiting chemokines, Cxcl10 and Cxcl11, IFN-induced molecules, MX dynamin-like GTPase 1 (Mx1) and 2'-5' oligoadenylate synthetase-like 1 (Oasl1), nitric oxide synthase 2 (Nos2), and interferon beta 1 (Ifnb1). These results indicate that the STING-triggered tumor-migrating Mφ participate in the anti-tumor effects of STING-activating compounds.
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1, Asahikawa, 078-8510, Japan. ohkurit@asahikawa-med.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohkuri
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Kosaka
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1, Asahikawa, 078-8510, Japan.|Respiratory and Breast Center, Asahikawa Medical University Hospital, Asahikawa, 078-8510, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ishibashi
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1, Asahikawa, 078-8510, Japan.|Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, 078-8510, Japan.|Cancer Immunology, Inflammation and Tolerance Program, Augusta University GRU Cancer Center, Augusta, GA, 30912, USA.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kumai
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1, Asahikawa, 078-8510, Japan.|Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, 078-8510, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1, Asahikawa, 078-8510, Japan.|Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, 078-8510, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Ohara
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, 078-8510, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nagato
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Oikawa
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Aoki
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, 078-8510, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Harabuchi
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Augusta University GRU Cancer Center, Augusta, GA, 30912, USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1, Asahikawa, 078-8510, Japan. hiroya@asahikawa-med.ac.jp.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D005260:Female; D007167:Immunotherapy; D015552:Injections, Intralesional; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009712:Nucleotides, Cyclic / Q000008:administration & dosage* / Q000494:pharmacology; D010587:Phagocytosis
chemical_list: D000970:Antineoplastic Agents; D009712:Nucleotides, Cyclic; C584311:cyclic guanosine monophosphate-adenosine monophosphate
keywords: Immunotherapy; Macrophages; STING; Tumor migration; cGAMP