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

Marino Nagata, Akemi Kosaka, Yuki Yajima, Syunsuke Yasuda, Mizuho Ohara, Kenzo Ohara, Shohei Harabuchi, Ryusuke Hayashi, Hiroshi Funakoshi, Jun Ueda, Takumi Kumai, Toshihiro Nagato, Kensuke Oikawa, Yasuaki Harabuchi, Celis Esteban, Takayuki Ohkuri, Hiroya Kobayashi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2301-2312
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume70
Issue number8
DOIs
StatePublished - Aug 2021

Keywords

  • CXCR2
  • Cancer immunity cycle
  • Neutrophils
  • Stimulator of interferon genes
  • Type I interferons
  • cGAMP

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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