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  3. Enhancing anti-tumor immunity of natural killer cells through targeting IL-15R signaling

Enhancing anti-tumor immunity of natural killer cells through targeting IL-15R signaling

  • Cancer Cell. 2025 Jun 10:S1535-6108(25)00220-X. doi: 10.1016/j.ccell.2025.05.011.
Iva Nikolic 1,  Joseph Cursons 1,  Benjamin Shields 1,  Stephane Chappaz 1,  Harrison Sudholz 2,  Xiangpeng Meng 2,  Patrick Constantinescu 1,  Reshma Vijayakumaran 1,  Michael D'Angelo 1,  Momeneh Foroutan 1,  David Ladd 1,  Matthew Veldman 1,  Jason Glab 1,  Tahlia Procter 1,  Hae-Young Park 2,  Julian Contet 1,  Felix Deuss 1,  Kahlia Wong 1,  Yi Sun 3,  Richard Berry 1,  Jai Rautela 4,  Nicholas D Huntington 5
Affiliations

Affiliations

  • 1 oNKo-innate Pty Ltd., Moonee Ponds, VIC 3039, Australia.
  • 2 Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
  • 3 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 oNKo-innate Pty Ltd., Moonee Ponds, VIC 3039, Australia. Electronic address: jai@onko-innate.com.
  • 5 oNKo-innate Pty Ltd., Moonee Ponds, VIC 3039, Australia; Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. Electronic address: nicholas.huntington@monash.edu.
PMID: 40513576 DOI: 10.1016/j.ccell.2025.05.011
Abstract

Interleukin-15 receptor (IL-15R) agonists induce anti-tumor immunity in pre-clinical models. However, dose-limiting toxicity has hampered their clinical development. We performed genome-wide CRISPR screens to reveal the complete IL-15R signaling mechanism in natural killer (NK) cells and discovered that ubiquitin-dependent IL-15R degradation is the dominant mechanism restraining IL-15R signaling. Key hits included the NEDD8 E2-conjugating enzyme UBE2F, the ubiquitin E3-ligase ARIH2, and Cullin-5 RING E3 Ligase (CRL5) members. We found that UBE2F was required for neddylation and activation of CUL5, whereas ARIH2 contributed to CRL5-mediated IL-15RB degradation. Ablation of ARIH2 or UBE2F increased IL-15RB surface expression and enhanced signaling, resulting in proinflammatory cytokine production and augmented natural and CAR-mediated cytotoxicity. In mice lacking Arih2, Rnf7, or Ube2f, we observed that the IL-15R hyperresponsive NK cells exhibited superior in vivo anti-tumor immunity against primary and disseminated metastatic tumors. Thus, we have identified the Enzymes UBE2F and ARIH2 as tractable immunotherapy drug targets.

Keywords

CRISPR screening; cytokine receptors; cytokine signaling; interleukin-15; natural killer cells; post-translational modifications.

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