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

Autor: Dubrot J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain., Du PP; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanford University School of Medicine, Stanford, CA, USA., Lane-Reticker SK; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kessler EA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Muscato AJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Mehta A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Freeman SS; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Allen PM; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Olander KE; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ockerman KM; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Wolfe CH; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Wiesmann F; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Knudsen NH; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Tsao HW; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Iracheta-Vellve A; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Schneider EM; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Rivera-Rosario AN; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kohnle IC; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Pope HW; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ayer A; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Mishra G; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Zimmer MD; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kim SY; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Mahapatra A; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ebrahimi-Nik H; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Frederick DT; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA., Boland GM; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Surgery, Massachusetts General Hospital, Boston, MA, USA., Haining WN; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.; ArsenalBio, South San Francisco, CA, USA., Root DE; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Doench JG; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Hacohen N; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Yates KB; Broad Institute of MIT and Harvard, Cambridge, MA, USA. yates@broadinstitute.org.; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. yates@broadinstitute.org.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. yates@broadinstitute.org., Manguso RT; Broad Institute of MIT and Harvard, Cambridge, MA, USA. rmanguso@mgh.harvard.edu.; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. rmanguso@mgh.harvard.edu.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. rmanguso@mgh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2022 Oct; Vol. 23 (10), pp. 1495-1506. Date of Electronic Publication: 2022 Sep 23.
DOI: 10.1038/s41590-022-01315-x
Abstrakt: 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.
(© 2022. Springer Nature America, Inc.)
Databáze: MEDLINE
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