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A critical role of STING-triggered tumor-migrating neutrophils for anti-tumor effect of intratumoral cGAMP treatment

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Abstract

Stimulator of interferon genes (STING) contributes to anti-tumor immunity by activating antigen-presenting cells and inducing mobilization of tumor-specific T cells. A role for tumor-migrating neutrophils in the anti-tumor effect of STING-activating therapy has not been defined. We used mouse tumor transplantation models for assessing neutrophil migration into the tumor triggered by intratumoral treatment with STING agonist, 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Intratumoral STING activation with cGAMP enhanced neutrophil migration into the tumor in an NF-κB/CXCL1/2-dependent manner. Blocking the neutrophil migration by anti-CXCR2 monoclonal antibody impaired T cell activation in tumor-draining lymph nodes (dLNs) and efficacy of intratumoral cGAMP treatment. Moreover, the intratumoral cGAMP treatment did not show any anti-tumor effect in type I interferon (IFN) signal-impaired mice in spite of enhanced neutrophil accumulation in the tumor. These results suggest that both neutrophil migration and type I interferon (IFN) induction by intratumoral cGAMP treatment were critical for T-cell activation of dLNs and the anti-tumor effect. In addition, we also performed in vitro analysis showing enhanced cytotoxicity of neutrophils by IFN-β1. Extrinsic STING activation triggers anti-tumor immune responses by recruiting and activating neutrophils in the tumor via two signaling pathways, CXCL1/2 and type I IFNs.

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Data availability

All data and materials generated during the current study are available from the corresponding authors upon reasonable request.

Abbreviations

CD:

Cluster of differentiation

CXCL:

Chemokine (C-X-C motif) ligand

CXCR:

CXC chemokine receptor

mAb:

Monoclonal antibody

NF-κB:

Nuclear factor-kappa B

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Acknowledgments

The authors thank Dr. Tadatsugu Taniguchi for providing IRF3-KO and IRF7-KO and 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. This work was supported by the Akiyama Life Science Foundation to T. Ohkuri.

Funding

This study was supported by the grants from the Akiyama Life Science Foundation (T. Ohkuri).

Author information

Authors and Affiliations

  1. Department of Pathology, Asahikawa Medical University, Asahikawa, Hokkaido, 078-8510, Japan

    Marino Nagata, Akemi Kosaka, Yuki Yajima, Syunsuke Yasuda, Mizuho Ohara, Kenzo Ohara, Shohei Harabuchi, Ryusuke Hayashi, Toshihiro Nagato, Kensuke Oikawa, Takayuki Ohkuri & Hiroya Kobayashi

  2. Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, 078-8510, Japan

    Kenzo Ohara, Shohei Harabuchi, Ryusuke Hayashi, Takumi Kumai & Yasuaki Harabuchi

  3. Deprtment of Advanced Medical Science, Asahikawa Medical University, Asahikawa, Hokkaido, 078-8510, Japan

    Hiroshi Funakoshi & Jun Ueda

  4. Georgia Cancer Center, Augusta University Medical College of Georgia, Augusta, GA, USA

    Celis Esteban

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  1. Marino Nagata
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Contributions

MN, AK, TO, and HK designed and preformed experiments; MN and TO analyzed results and made the figures; JU and HF generated IFNAR1KO mice; MN, AK, TO, YY, SY, MO, KO, SH, RH, TK, TN, KO, NA, YH, CE, and H.K. discussed the results; MN, TO, and HK wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Takayuki Ohkuri or Hiroya Kobayashi.

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The authors declare no competing interests.

Ethics approval

Animal use protocol was approved by the Asahikawa Medical University Institutional Animal Care and Use Committee (approval no. 19111). This study was performed in accordance with the Declaration of Helsinki.

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All data and materials generated during the current study are available from the corresponding authors upon reasonable request.

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Nagata, M., Kosaka, A., Yajima, Y. et al. A critical role of STING-triggered tumor-migrating neutrophils for anti-tumor effect of intratumoral cGAMP treatment. Cancer Immunol Immunother 70, 2301–2312 (2021). https://doi.org/10.1007/s00262-021-02864-0

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