In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer

• Published in: Nature immunology Vol. 23; no. 10; pp. 1495 - 1506
• Main Authors: Dubrot, Juan, Du, Peter P., Lane-Reticker, Sarah Kate, Kessler, Emily A., Muscato, Audrey J., Mehta, Arnav, Freeman, Samuel S., Allen, Peter M., Olander, Kira E., Ockerman, Kyle M., Wolfe, Clara H., Wiesmann, Fabius, Knudsen, Nelson H., Tsao, Hsiao-Wei, Iracheta-Vellve, Arvin, Schneider, Emily M., Rivera-Rosario, Andrea N., Kohnle, Ian C., Pope, Hans W., Ayer, Austin, Mishra, Gargi, Zimmer, Margaret D., Kim, Sarah Y., Mahapatra, Animesh, Ebrahimi-Nik, Hakimeh, Frederick, Dennie T., Boland, Genevieve M., Haining, W. Nicholas, Root, David E., Doench, John G., Hacohen, Nir, Yates, Kathleen B., Manguso, Robert T.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2022; Nature Publishing Group
• Subjects: 631/250/21/324/1509; 631/250/580; 631/67/1059/2325; 631/67/580; Biomedical and Life Sciences; Biomedicine; Cancer; CD8 antigen; CD8-Positive T-Lymphocytes; Clustered Regularly Interspaced Short Palindromic Repeats - genetics; CRISPR; Genomes; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - metabolism; Humans; Immune checkpoint; Immune Checkpoint Inhibitors; Immune Evasion; Immune system; Immunology; Infectious Diseases; Interferon; Interferon-gamma - genetics; Interferon-gamma - metabolism; Kidney cancer; Lymphocytes T; Major histocompatibility complex; Melanoma; Natural killer cells; Neoplasms; NK Cell Lectin-Like Receptor Subfamily C; Renal cell carcinoma; Resource; Tumors; γ-Interferon
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-022-01315-x

The immune system can eliminate tumors, but checkpoints enable immune escape. Here, we identify immune evasion mechanisms using genome-scale in vivo CRISPR screens across cancer models treated with immune checkpoint blockade (ICB). We identify immune evasion genes and important immune inhibitory checkpoints conserved across cancers, including the non-classical major histocompatibility complex class I (MHC class I) molecule Qa-1 b /HLA-E. Surprisingly, loss of tumor interferon-γ (IFNγ) signaling sensitizes many models to immunity. The immune inhibitory effects of tumor IFN sensing are mediated through two mechanisms. First, tumor upregulation of classical MHC class I inhibits natural killer cells. Second, IFN-induced expression of Qa-1 b inhibits CD8 + T cells via the NKG2A/CD94 receptor, which is induced by ICB. Finally, we show that strong IFN signatures are associated with poor response to ICB in individuals with renal cell carcinoma or melanoma. This study reveals that IFN-mediated upregulation of classical and non-classical MHC class I inhibitory checkpoints can facilitate immune escape. Here, the authors use genome-scale in vivo CRISPR screens to look at immune evasion mechanisms across cancer models, showing that IFN-mediated upregulation of classical and non-classical MHC class I inhibitory checkpoints facilitate immune escape.