TY - JOUR
T1 - Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site
AU - Ohkuri, Takayuki
AU - Kosaka, Akemi
AU - Ishibashi, Kei
AU - Kumai, Takumi
AU - Hirata, Yui
AU - Ohara, Kenzo
AU - Nagato, Toshihiro
AU - Oikawa, Kensuke
AU - Aoki, Naoko
AU - Harabuchi, Yasuaki
AU - Celis, Esteban
AU - Kobayashi, Hiroya
N1 - Funding Information:
The authors thank Mr. Hayakawa Toshiyuki and Ms. Hino Chihiro (at the Animal Laboratory for Medical Research, Center for Advanced Research and Education, Asahikawa Medical University) and Ms. Matsumoto Rie (at the Department of Pathology, Asahikawa Medical University) for devotedly maintaining the mice and Mr. Akutsu Hiroaki (at Center for Advanced Research and Education, Asahikawa Medical University) for technically supporting cell sorting. This work was supported by grants from Japan Society for the Promotion of Science KAKENHI Grant Number 16K19070 (Ohkuri) and 16K19071 (Kosaka), the Akiyama Life Science Foundation (Ohkuri), and Innovative Research in Life Science from Asahikawa Medical University (Ohkuri and Kosaka). Ohkuri and Kosaka preformed experiments, analyzed results, and made the figures; Ohkuri, Kosaka, Ishibashi, Kumai, Hirata, Ohara, Nagato, Oikawa, Aoki, Harabuchi, Celis, and Kobayashi discussed the results; Ohkuri, Kosaka, Celis, and Kobayashi designed the research and wrote the paper. The authors declare no competing financial interests.
Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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+ CD11bmid Ly6C+ 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.
AB - 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+ CD11bmid Ly6C+ 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.
KW - Immunotherapy
KW - Macrophages
KW - STING
KW - Tumor migration
KW - cGAMP
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UR - http://www.scopus.com/inward/citedby.url?scp=85014042994&partnerID=8YFLogxK
U2 - 10.1007/s00262-017-1975-1
DO - 10.1007/s00262-017-1975-1
M3 - Article
C2 - 28243692
AN - SCOPUS:85014042994
SN - 0340-7004
VL - 66
SP - 705
EP - 716
JO - Cancer Immunology, Immunotherapy
JF - Cancer Immunology, Immunotherapy
IS - 6
ER -