1. HOIP limits anti‐tumor immunity by protecting against combined TNF and IFN‐gamma‐induced apoptosis.
- Author
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Freeman, Andrew J, Vervoort, Stephin J, Michie, Jessica, Ramsbottom, Kelly M, Silke, John, Kearney, Conor J, and Oliaro, Jane
- Abstract
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. Synopsis: HOIP protects tumor cells from apoptosis induced by combined TNF and IFN‐γ co‐secreted by NK and CD8+ T cells. HOIP inhibition might thus be a strategy to enhance immunotherapy responses. HOIP limits tumor sensitivity to both NK and CD8+ T cell cytotoxicity.HOIP mediates this activity through protecting against apoptosis induced by combined TNF and IFN‐γ.HOIP limits combined TNF‐ and IFN‐γ‐induced apoptosis, that engages extrinsic and intrinsic apoptotic effectors.HOIP inhibition sensitizes tumor cells to combined TNF and IFN‐γ, and T cell derived co‐culture supernatants. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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