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

Juan Dubrot^#^{1

2

3

4}, Peter P Du^#^{1

5}, Sarah Kate Lane-Reticker¹, Emily A Kessler¹, Audrey J Muscato¹, Arnav Mehta^{1

2

3}, Samuel S Freeman^{1

2

3}, Peter M Allen¹, Kira E Olander¹, Kyle M Ockerman¹, Clara H Wolfe¹, Fabius Wiesmann¹, Nelson H Knudsen^{1

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 Frederick^{2

3

6}, Genevieve M Boland^{2

3

6}, W Nicholas Haining^{1

7

8}, David E Root¹, John G Doench¹, Nir Hacohen^{1

2

3}, Kathleen B Yates^{9

10

11}, Robert T Manguso^{12

13

14}

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
³ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
⁵ Stanford University School of Medicine, Stanford, CA, USA.
⁶ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁸ ArsenalBio, South San Francisco, CA, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. yates@broadinstitute.org.
¹⁰ Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. yates@broadinstitute.org.
¹¹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. yates@broadinstitute.org.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA. rmanguso@mgh.harvard.edu.
¹³ Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. rmanguso@mgh.harvard.edu.
¹⁴ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. rmanguso@mgh.harvard.edu.

^# Contributed equally.

PMID: 36151395
DOI: 10.1038/s41590-022-01315-x

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

Juan Dubrot et al. Nat Immunol. 2022 Oct.

. 2022 Oct;23(10):1495-1506.

doi: 10.1038/s41590-022-01315-x. Epub 2022 Sep 23.

Authors

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
³ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
⁵ Stanford University School of Medicine, Stanford, CA, USA.
⁶ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁸ ArsenalBio, South San Francisco, CA, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. yates@broadinstitute.org.
¹⁰ Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. yates@broadinstitute.org.
¹¹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. yates@broadinstitute.org.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA. rmanguso@mgh.harvard.edu.
¹³ Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. rmanguso@mgh.harvard.edu.
¹⁴ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. rmanguso@mgh.harvard.edu.

^# Contributed equally.

PMID: 36151395
DOI: 10.1038/s41590-022-01315-x

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-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.

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References

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

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

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Molecular Biology Databases

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