Tumor immune evasion arises through loss of TNF sensitivity

Conor J. Kearney, Stephin J. Vervoort, Simon J. Hogg, Kelly M. Ramsbottom, Andrew J. Freeman, Najoua Lalaoui, Lizzy Pijpers, Jessica Michie, Kristin K. Brown, Deborah A. Knight, Vivien Sutton, Paul A. Beavis, Ilia Voskoboinik, Phil K. Darcy, John Silke, Joseph A. Trapani, Ricky W. Johnstone, Jane Oliaro

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254 Citations (Scopus)

Abstract

Immunotherapy has revolutionized outcomes for cancer patients, but the mechanisms of resistance remain poorly defined. We used a series of whole-genome clustered regularly interspaced short palindromic repeat (CRISPR)–based screens performed in vitro and in vivo to identify mechanisms of tumor immune evasion from cytotoxic lymphocytes [CD8+ T cells and natural killer (NK) cells]. Deletion of key genes within the tumor necrosis factor (TNF) signaling, interferon- (IFN-) signaling, and antigen presentation pathways provided protection of tumor cells from CD8+ T cell–mediated killing and blunted antitumor immune responses in vivo. Deletion of a number of genes in the TNF pathway also emerged as the key mechanism of immune evasion from primary NK cells. Our screens also identified that the metabolic protein 2-aminoethanethiol dioxygenase (Ado) modulates sensitivity to TNF-mediated killing by cytotoxic lymphocytes and is required for optimal control of tumors in vivo. Remarkably, we found that tumors delete the same genes when exposed to perforin-deficient CD8+ T cells, demonstrating that the dominant immune evasion strategy used by tumor cells is acquired resistance to T cell–derived cytokine-mediated antitumor effects. We demonstrate that TNF-mediated bystander killing is a potent T cell effector mechanism capable of killing antigen-negative tumor cells. In addition to highlighting the importance of TNF in CD8+ T cell– and NK cell–mediated killing of tumor cells, our study also provides a comprehensive picture of the roles of the TNF, IFN, and antigen presentation pathways in immune-mediated tumor surveillance.

Original languageEnglish
Article numbereaar3451
Number of pages14
JournalScience Immunology
Volume3
Issue number23
DOIs
Publication statusPublished - May 2018
Externally publishedYes

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