HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma-induced apoptosis.

Autor: Freeman AJ; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia., Vervoort SJ; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia.; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, Vic., Australia., Michie J; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia., Ramsbottom KM; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia., Silke J; Inflammation Department, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, Vic., Australia., Kearney CJ; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia.; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, Vic., Australia., Oliaro J; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia.; Department of Immunology and Pathology, Monash University, Melbourne, Vic., Australia.
Jazyk: angličtina
Zdroj: EMBO reports [EMBO Rep] 2021 Nov 04; Vol. 22 (11), pp. e53391. Date of Electronic Publication: 2021 Sep 01.
DOI: 10.15252/embr.202153391
Abstrakt: 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.
(© 2021 The Authors.)
Databáze: MEDLINE
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