Tumor immune evasion arises through loss of TNF sensitivity
- Kearney, CJ; Vervoort, SJ; Hogg, SJ; Ramsbottom, KM; Freeman, AJ; Lalaoui, N; Pijpers, L; Michie, J; Brown, KK; Knight, DA; Sutton, V; Beavis, PA; Voskoboinik, I; Darcy, PK; Silke, J; Trapani, JA; Johnstone, RW; Oliaro, J;
Publication Year 2018-05-18, Volume 3, Issue #23, Page pii: eaar3451
- Journal Title
- Science Immunology
- Publication Type
- Journal Article
- 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-gamma (IFN-gamma) 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.
- WEHI Research Division(s)
- Cell Signalling And Cell Death
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-05-31 09:17:46Last Modified: 2018-05-31 09:29:14