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Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade

Hang Zhou1, Wenjun Wang2, Hairong Xu1

  • 1Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

Nature Communications
|July 9, 2024
PubMed

Insights

Type I interferons reprogram tumor cell metabolism, activating oxidative phosphorylation and autophagy. This enhances CD47-SIRPα blockade immunotherapy by increasing extracellular ATP, crucial for T cell responses.

Area of Science:

  • Immunology
  • Cancer Biology
  • Metabolic Reprogramming

Background:

  • Type I interferons are known for immune cell roles in tumor immunotherapy.
  • Direct effects of type I interferons on tumor cells, particularly metabolic reprogramming, are less understood.
  • The potential of targeting oxidative phosphorylation in tumor cells for immunotherapy remains unclear.

Purpose of the Study:

  • Investigate the direct effects of type I interferons on tumor cells in the context of CD47-SIRPα blockade immunotherapy.
  • Elucidate the metabolic mechanisms by which type I interferons influence immunotherapy efficacy.
  • Explore novel therapeutic strategies combining CD47-SIRPα blockade with metabolic interventions.

Main Methods:

  • Utilized mouse models of CD47-SIRPα blockade immunotherapy.
  • Assessed the role of type I interferons and tumor cell metabolism (oxidative phosphorylation, autophagy) in immunotherapy response.
  • Investigated extracellular ATP release and its role in immune cell activation.
  • Evaluated combination therapies involving CD47-SIRPα blockade and inhibitors of ATP-degrading ectoenzymes (CD39, CD73).

Main Results:

  • Tumor cell responsiveness to type I interferons, but not type II, is essential for CD47-SIRPα blockade efficacy.
  • Type I interferons directly activate tumor cell oxidative phosphorylation and enhance secretory autophagy in an ISG15-dependent manner.
  • Genetic deficiency in oxidative phosphorylation or autophagy renders tumor cells resistant to CD47-SIRPα blockade.
  • Released extracellular ATP activates dendritic cells via the P2X7 receptor, promoting antitumor T cell responses.
  • Combination therapy with CD39/CD73 inhibitors synergizes with CD47-SIRPα blockade to enhance antitumor effects.

Conclusions:

  • Type I interferons play a critical role in reprogramming tumor cell metabolism, specifically activating oxidative phosphorylation and autophagy.
  • This metabolic reprogramming is essential for the efficacy of CD47-SIRPα blockade immunotherapy.
  • Targeting tumor cell metabolism and extracellular ATP degradation offers promising strategies to enhance cancer immunotherapy.

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