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In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer.
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.
  • Dubrot J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Du PP; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
  • Lane-Reticker SK; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Kessler EA; Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • Muscato AJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Mehta A; Stanford University School of Medicine, Stanford, CA, USA.
  • Freeman SS; Broad Institute of MIT and Harvard, Cambridge, 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; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
  • Wiesmann F; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Knudsen NH; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Tsao HW; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
  • Iracheta-Vellve A; Department of Medicine, Massachusetts General Hospital, Boston, 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; Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
  • Kim SY; Department of Medicine, Massachusetts General Hospital, Boston, 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; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Boland GM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Haining WN; Broad Institute of MIT and Harvard, Cambridge, MA, 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.
  • Yates KB; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Manguso RT; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Immunol ; 23(10): 1495-1506, 2022 10.
Article en En | MEDLINE | ID: mdl-36151395
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Linfocitos T CD8-positivos / Neoplasias Límite: Humans Idioma: En Año: 2022 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Linfocitos T CD8-positivos / Neoplasias Límite: Humans Idioma: En Año: 2022 Tipo del documento: Article