Journal article

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

Andrew J Freeman, Stephin J Vervoort, Jessica Michie, Kelly M Ramsbottom, John Silke, Conor J Kearney, Jane Oliaro

EMBO REPORTS | WILEY | Published : 2021

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, inv..

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Grants

Awarded by NHMRC


Awarded by National Breast Cancer Foundation


Funding Acknowledgements

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.