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CIS is a potent checkpoint in NK cell-mediated tumor immunity

Rebecca B Delconte1,2, Tatiana B Kolesnik1, Laura F Dagley1,2

  • 1The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Nature Immunology
|May 24, 2016
PubMed

Insights

Cytokine-inducible SH2-containing protein (CIS) negatively regulates natural killer (NK) cell signaling. Deleting CIS enhances NK cell anti-tumor activity, revealing a new target for cancer immunotherapy.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Natural killer (NK) cells detect aberrant cells via activating and inhibitory signals, modulated by cytokines like IL-15.
  • Understanding NK cell regulation is crucial for developing effective cancer immunotherapies.

Purpose of the Study:

  • To identify novel regulators of IL-15 signaling in NK cells.
  • To investigate the role of cytokine-inducible SH2-containing protein (CIS) in NK cell-mediated anti-tumor immunity.

Main Methods:

  • Investigated the function of CIS (encoded by Cish) in IL-15 signaling using Cish-deleted NK cells.
  • Analyzed JAK-STAT signaling pathways and CIS interaction with JAK1.
  • Assessed NK cell proliferation, survival, IFN-γ production, cytotoxicity, and tumor metastasis in Cish(-/-) mice.

Main Results:

  • CIS acts as a critical negative regulator of IL-15 signaling in NK cells.
  • Deletion of Cish leads to enhanced NK cell proliferation, survival, IFN-γ production, and cytotoxicity.
  • CIS inhibits JAK1 activity and promotes its proteasomal degradation, dampening JAK-STAT signaling.
  • Cish(-/-) mice exhibit resistance to melanoma, prostate, and breast cancer metastasis due to enhanced NK cell activity.

Conclusions:

  • CIS is a key intracellular checkpoint controlling NK cell-mediated tumor immunity.
  • Blocking CIS function presents a potential strategy for novel cancer immunotherapies targeting NK cell activity.

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