Tumor immune evasion arises through loss of TNF sensitivity Academic Article uri icon

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-γ (IFN-γ) 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.

authors

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

publication date

  • 2018