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TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity

Jiacheng Bi1, Chen Cheng1, Chaoyue Zheng1

  • 1CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.

Science Advances
|September 15, 2021
PubMed

Insights

Tumor immunity is enhanced by targeting TIPE2, a novel checkpoint regulating natural killer (NK) cell maturation. TIPE2 deficiency boosts NK cell function and IL-15 response, offering a promising immunotherapy strategy.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Interleukin-15 (IL-15) is crucial for natural killer (NK) cell maturation and function.
  • Few specific checkpoints regulating NK cell ontogenesis and maturation have been identified.
  • Understanding NK cell maturation pathways is key to developing effective immunotherapies.

Purpose of the Study:

  • To investigate the role of TIPE2 in NK cell maturation and function.
  • To explore the potential of targeting TIPE2 for enhancing antitumor immunity.
  • To elucidate the molecular mechanisms by which TIPE2 influences NK cell responses.

Main Methods:

  • Analysis of TIPE2 expression during NK cell ontogenesis in mice and humans.
  • Generation and characterization of NK cell-specific TIPE2-deficient mice.
  • Assessment of NK cell activation, cytotoxicity, and cytokine production.
  • Investigation of the IL-15 signaling pathway and mTOR activity.
  • Evaluation of tumor growth in TIPE2-deficient and wild-type mice.

Main Results:

  • TIPE2 expression increases with NK cell maturation in both mice and humans.
  • NK-specific TIPE2 deficiency leads to increased mature NK cells with enhanced activation, cytotoxicity, and IFN-γ production.
  • TIPE2 deficiency enhances NK cell response to IL-15 for maturation.
  • TIPE2 suppresses IL-15-triggered mTOR activity in NK cells.
  • Blocking mTOR partially reverses the effects of TIPE2 deficiency on NK cell maturation.
  • NK-specific TIPE2-deficient mice exhibit resistance to tumor growth in vivo.

Conclusions:

  • TIPE2 acts as a critical checkpoint in NK cell maturation and antitumor immunity.
  • Targeting TIPE2 enhances NK cell function and improves resistance to tumor growth.
  • TIPE2 modulation represents a promising strategy for NK cell-based immunotherapies.

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