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Systematic identification of cancer cell vulnerabilities to natural killer cell-mediated immune surveillance

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Cite this article as: eLife 2019;8:e47362 doi: 10.7554/eLife.47362

Abstract

Only a subset of cancer patients respond to T-cell checkpoint inhibitors, highlighting the need for alternative immunotherapeutics. We performed CRISPR-Cas9 screens in a leukemia cell line to identify perturbations that enhance natural killer effector functions. Our screens defined critical components of the tumor-immune synapse and highlighted the importance of cancer cell interferon-g signaling in modulating NK activity. Surprisingly, disrupting the ubiquitin ligase substrate adaptor DCAF15 strongly sensitized cancer cells to NK-mediated clearance. DCAF15 disruption induced an inflamed state in leukemic cells, including increased expression of lymphocyte costimulatory molecules. Proteomic and biochemical analysis revealed that cohesin complex members were endogenous client substrates of DCAF15. Genetic disruption of DCAF15 was phenocopied by treatment with indisulam, an anticancer drug that functions through DCAF15 engagement. In AML patients, reduced DCAF15 expression was associated with improved survival. These findings suggest that DCAF15 inhibition may have useful immunomodulatory properties in the treatment of myeloid neoplasms.

Article and author information

Author details

  1. Matthew Pech

    Department of Oncology, Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Matthew Pech, employee of Calico Life Sciences, LLC.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1451-0234
  2. Linda E Fong

    Department of Oncology, Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Linda E Fong, employee of Calico Life Sciences, LLC.
  3. Jacqueline E Villalta

    Department of Oncology, Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Jacqueline E Villalta, employee of Calico Life Sciences, LLC.
  4. Leanne JG Chan

    Department of Proteomics, Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Leanne JG Chan, employee of Calico Life Sciences, LLC.
  5. Samir Kharbanda

    Department of Oncology, Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Samir Kharbanda, employee of Calico Life Sciences, LLC.
  6. Jonathon J O'Brien

    Department of Proteomics, Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Jonathon J O'Brien, employee of Calico Life Sciences, LLC.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9660-4797
  7. Fiona E McAllister

    Department of Proteomics, Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Fiona E McAllister, employee of Calico Life Sciences, LLC.
  8. Ari J. Firestone

    Department of Oncology, Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Ari J. Firestone, employee of Calico Life Sciences, LLC.
  9. Calvin H Jan

    Department of Research, Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Calvin H Jan, employee of Calico Life Sciences, LLC.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9033-4028
  10. Jeffrey Settleman

    Department of Oncology, Calico Life Sciences LLC, San Diego, United States
    For correspondence
    jsettleman@gmail.com
    Competing interests
    Jeffrey Settleman, employee of Calico Life Sciences, LLC; Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3569-6493

Funding

Calico Life Sciences LLC

  • Matthew Pech
  • Linda E Fong
  • Jacqueline E Villalta
  • Leanne JG Chan
  • Samir Kharbanda
  • Jonathon J O'Brien
  • Fiona E McAllister
  • Ari J. Firestone
  • Calvin H Jan
  • Jeffrey Settleman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Stipan Jonjic, University Rijeka, Croatia

Publication history

  1. Received: April 3, 2019
  2. Accepted: August 2, 2019
  3. Accepted Manuscript published: August 27, 2019 (version 1)
  4. Version of Record published: August 28, 2019 (version 2)
  5. Version of Record updated: September 10, 2019 (version 3)

Copyright

© 2019, Pech et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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