UBE2F inhibits Natural Killer cell tumor immunity by activating the ARIH2-CRL5 complex to degrade interleukin 15 receptors

Interleukin-15 receptor (IL-15R) agonists induce anti-tumor immunity in pre-clinical models, however, dose-limiting toxicity has hampered their clinical development. An alternative is to target pathways downstream of the IL-15R to access different therapeutic profiles. We performed genome-wide CRISPR screens to reveal the complete IL15R signaling mechanism in NK cells and discovered ubiquitin-dependent IL15R degradation as the dominant mechanism restraining IL-15R signaling. Top hits included the NEDD8 E2conjugating enzyme UBE2F & ubiquitin E3-ligase ARIH2, along with Cullin-5 RING E3 Ligase (CRL5) members. UBE2F was required for CUL5 neddylation/activation whereas ARIH2 contributed to CRL5-mediated IL-15RB degradation. Ablation of ARIH2 or UBE2F enhanced IL-15RB surface expression/signaling & proinflammatory cytokine production, and augmented natural & CAR-mediated cytotoxicity. In mice lacking Arih2, Rnf7 or Ube2f, IL-15R hyperresponsive NK cells resulted in 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.