Publicaciones científicas

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

23-oct-2022 | Revista: Nature Immunology

Juan Dubrot # 1 2 3 4, Peter P Du # 1 5, Sarah Kate Lane-Reticker 1, Emily A Kessler 1, Audrey J Muscato 1, Arnav Mehta 1 2 3, Samuel S Freeman 1 2 3, Peter M Allen 1, Kira E Olander 1, Kyle M Ockerman 1, Clara H Wolfe 1, Fabius Wiesmann 1, Nelson H Knudsen 1 2 3, Hsiao-Wei Tsao 1, Arvin Iracheta-Vellve 1, Emily M Schneider 1, Andrea N Rivera-Rosario 1, Ian C Kohnle 1, Hans W Pope 1, Austin Ayer 1, Gargi Mishra 1, Margaret D Zimmer 1, Sarah Y Kim 1, Animesh Mahapatra 1, Hakimeh Ebrahimi-Nik 1, Dennie T Frederick 2 3 6, Genevieve M Boland 2 3 6, W Nicholas Haining 1 7 8, David E Root 1, John G Doench 1, Nir Hacohen 1 2 3, Kathleen B Yates 9 10 11, Robert T Manguso 12 13 14


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, tumor interferon-γ (IFNγ) signaling loss 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 ICB induces. 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.

CITA DEL ARTÍCULO  Nat Immunol. 2022 Oct;23(10):1495-1506. doi: 10.1038/s41590-022-01315-x. Epub 2022 Sep 23.