Poster Presentation Melbourne Immunotherapy Network Winter Symposium 2021

HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma induced apoptosis (#110)

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 mechanisms by which tumors evade immunity. Using a series of genome-scale CRISPR/Cas9 screens, we reveal that melanoma cells lacking HOIP, the catalytic subunit of the linear ubiquitin assembly complex, are highly susceptible to both NK and CD8+ T cell-mediated killing. This was due to increased sensitivity to the combined effect of the inflammatory cytokines, TNF and IFN-γ, released by NK and CD8+ T cells upon target recognition. Indeed, either genetic deletion or pharmacological inhibition of HOIP augmented tumor sensitivity to combined TNF and IFN-γ induced cell death. Together, we unveil a protective regulatory axis, involving tumor-expressed 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 untapped killing capacity of TNF and IFN-γ during immunotherapy.