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CIS IS A POTENT CHECKPOINT IN NK CELL ANTI-LEUKEMIA IMMUNITY
Author(s):
Nicholas Huntington
Nicholas Huntington
Affiliations:
Molecular Immunology,Walter and Eliza Hall,Parkville,Australia
(Abstract release date: 05/18/17) EHA Library. HUNTINGTON N. 06/25/17; 182102; S815
Nicholas HUNTINGTON
Nicholas HUNTINGTON
Contributions
PDF Abstract
Abstract

Abstract: S815

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:15 - 08:30

Location: Room N111

Background

 
 The detection of leukemia by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. 

Aims
We set out to identify the negative regultors of NK cell function in order to understand why immunogenic tumours and leukemia can evade or overcome NK cell detection and killing

Methods
We used a multidisciplinary approach including RNAseq, Mass Spectrometry, Structual biology, kinase enrichment and activity assays, NK cell in vitro analysis, biochemistry and de novo/experimental tumor/leukemia in vivo models

Results

 
 We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-gamma production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish−/− mice are resistant to leukemia in vivo, and this was independent of MHC-I expression.

Conclusion

 
 Our data uncover a potent intracellular checkpoint in NK cell–mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function. 

Session topic: 24. Gene therapy, cellular immunotherapy and vaccination

Keyword(s): NK cell, Immunotherapy, AML

Abstract: S815

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:15 - 08:30

Location: Room N111

Background

 
 The detection of leukemia by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. 

Aims
We set out to identify the negative regultors of NK cell function in order to understand why immunogenic tumours and leukemia can evade or overcome NK cell detection and killing

Methods
We used a multidisciplinary approach including RNAseq, Mass Spectrometry, Structual biology, kinase enrichment and activity assays, NK cell in vitro analysis, biochemistry and de novo/experimental tumor/leukemia in vivo models

Results

 
 We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-gamma production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish−/− mice are resistant to leukemia in vivo, and this was independent of MHC-I expression.

Conclusion

 
 Our data uncover a potent intracellular checkpoint in NK cell–mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function. 

Session topic: 24. Gene therapy, cellular immunotherapy and vaccination

Keyword(s): NK cell, Immunotherapy, AML

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