@article{fcf108caba774fb39a2aa2a46e200410,
title = "HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma-induced apoptosis",
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.",
keywords = "CRISPR screen, HOIP, IFN-gamma, immunotherapy, TNF",
author = "Freeman, {Andrew J.} and Vervoort, {Stephin J.} and Jessica Michie and Ramsbottom, {Kelly M.} and John Silke and Kearney, {Conor J.} and Jane Oliaro",
note = "Funding Information: For their resources and contributions to this work, we acknowledge the Australian Cancer Research Foundation and TCGA Research Network. We also acknowledge the following Peter MacCallum Cancer Centre Research Division cores: The Victorian Centre for Functional Genomics, Molecular Genomics, Flow Cytometry Facility, and Animal Facility. We thank Shirley Liu and Peng Jiang for kindly providing raw OT‐I B16‐F10 ova CRISPR/Cas9 screen data, Vivien Sutton for supply of OT‐I mice, and James Vince and colleagues at WEHI for helpful discussions. AJF was supported by scholarships from Australian Commonwealth Government, Steer North Australia, and the Peter MacCallum Cancer Foundation. CJK was supported by a NHMRC Early Career Fellowship. JO was supported by NHMRC (1139626) and National Breast Cancer Foundation (IIRS‐18‐151) project grants. Funding Information: For their resources and contributions to this work, we acknowledge the Australian Cancer Research Foundation and TCGA Research Network. We also acknowledge the following Peter MacCallum Cancer Centre Research Division cores: The Victorian Centre for Functional Genomics, Molecular Genomics, Flow Cytometry Facility, and Animal Facility. We thank Shirley Liu and Peng Jiang for kindly providing raw OT-I B16-F10 ova CRISPR/Cas9 screen data, Vivien Sutton for supply of OT-I mice, and James Vince and colleagues at WEHI for helpful discussions. AJF was supported by scholarships from Australian Commonwealth Government, Steer North Australia, and the Peter MacCallum Cancer Foundation. CJK was supported by a NHMRC Early Career Fellowship. JO was supported by NHMRC (1139626) and National Breast Cancer Foundation (IIRS-18-151) project grants. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = nov,
day = "4",
doi = "10.15252/embr.202153391",
language = "English",
volume = "22",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "EMBO Press",
number = "11",
}
