Immunity
Volume 47, Issue 2, 15 August 2017, Pages 363-373.e5
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Article
Dendritic Cells but Not Macrophages Sense Tumor Mitochondrial DNA for Cross-priming through Signal Regulatory Protein α Signaling

https://doi.org/10.1016/j.immuni.2017.07.016Get rights and content
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Highlights

  • DCs are specialized in DNA sensing through regulation of SIRPα signaling

  • Tumor-derived mtDNA is selectively increased in the cytosol of DCs after anti-CD47

  • Blocking SIRPα signaling on DCs limits the degradation of mtDNA

  • cGAS-mediated sensing triggered by mtDNA is required for anti-CD47 therapy

Summary

Inhibition of cytosolic DNA sensing represents a strategy that tumor cells use for immune evasion, but the underlying mechanisms are unclear. Here we have shown that CD47-signal regulatory protein α (SIRPα) axis dictates the fate of ingested DNA in DCs for immune evasion. Although macrophages were more potent in uptaking tumor DNA, increase of DNA sensing by blocking the interaction of SIRPα with CD47 preferentially occurred in dendritic cells (DCs) but not in macrophages. Mechanistically, CD47 blockade enabled the activation of NADPH oxidase NOX2 in DCs, which in turn inhibited phagosomal acidification and reduced the degradation of tumor mitochondrial DNA (mtDNA) in DCs. mtDNA was recognized by cyclic-GMP-AMP synthase (cGAS) in the DC cytosol, contributing to type I interferon (IFN) production and antitumor adaptive immunity. Thus, our findings have demonstrated how tumor cells inhibit innate sensing in DCs and suggested that the CD47-SIRPα axis is critical for DC-driven antitumor immunity.

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