Oral Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma-induced apoptosis (#20)

Andrew J Freeman 1 2 , Stephin J Vervoort 2 3 , Jessica Michie 1 2 , Kelly M Ramsbottom 1 , John Silke 4 5 , Conor J Kearney 2 3 , Jane Oliaro 1 2 6
  1. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  3. Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. Inflammation Department, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  5. Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
  6. Department of Immunology and Pathology, Monash University, Melbourne, VIC, Australia

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 whole-genome CRISPR/Cas9 screening, we reveal that melanoma cells lacking HOIP, the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC), are highly susceptible to both natural killer (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, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ), secreted by NK and CD8+ T cells upon target recognition. Both genetic deletion and pharmacological inhibition of HOIP augments tumor cell sensitivity to combined TNF and IFN-γ. Together, we unveil a protective regulatory HOIP-cytokine axis, 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/LUBAC inhibition as a potential strategy to harness and enhance the killing capacity of TNF and IFN-γ during immunotherapy, where amounts of these cytokines are elevated.