HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma-induced apoptosis
Journal Title
EMBO Reports
Publication Type
epub ahead of print
The success of cancer immunotherapy is limited to a subset of patients, highlighting the need to identify the processes by which tumors evade immunity. Using CRISPR/Cas9 screening, we reveal that melanoma cells lacking HOIP, the catalytic subunit of LUBAC, are highly susceptible to both NK and CD8(+) T-cell-mediated killing. We demonstrate that HOIP-deficient tumor cells exhibit increased sensitivity to the combined effect of the inflammatory cytokines, TNF and IFN-γ, released by NK and CD8(+) T cells upon target recognition. Both genetic deletion and pharmacological inhibition of HOIP augment tumor cell sensitivity to combined TNF and IFN-γ. Together, we unveil a protective regulatory axis, involving HOIP, which limits a transcription-dependent form of cell death that engages both intrinsic and extrinsic apoptotic machinery upon exposure to TNF and IFN-γ. Our findings highlight HOIP inhibition as a potential strategy to harness and enhance the killing capacity of TNF and IFN-γ during immunotherapy.
Embo Press
CRISPR screen; Hoip; IFN-gamma; Tnf; immunotherapy
WEHI Research Division(s)
PubMed ID
Rights Notice
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Creation Date: 2021-09-17 11:23:09
Last Modified: 2021-09-17 11:33:41
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