| Literature DB >> 36151395 |
Juan Dubrot1,2,3,4, Peter P Du1,5, Sarah Kate Lane-Reticker1, Emily A Kessler1, Audrey J Muscato1, Arnav Mehta1,2,3, Samuel S Freeman1,2,3, Peter M Allen1, Kira E Olander1, Kyle M Ockerman1, Clara H Wolfe1, Fabius Wiesmann1, Nelson H Knudsen1,2,3, Hsiao-Wei Tsao1, Arvin Iracheta-Vellve1, Emily M Schneider1, Andrea N Rivera-Rosario1, Ian C Kohnle1, Hans W Pope1, Austin Ayer1, Gargi Mishra1, Margaret D Zimmer1, Sarah Y Kim1, Animesh Mahapatra1, Hakimeh Ebrahimi-Nik1, Dennie T Frederick2,3,6, Genevieve M Boland2,3,6, W Nicholas Haining1,7,8, David E Root1, John G Doench1, Nir Hacohen1,2,3, Kathleen B Yates9,10,11, Robert T Manguso12,13,14.
Abstract
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-1b/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-1b 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.Entities:
Mesh：
Substances：
Year: 2022 PMID： 36151395 DOI： 10.1038/s41590-022-01315-x
Source DB: PubMed Journal: Nat Immunol ISSN： 1529-2908 Impact factor: 31.250