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

Abstract
Data availability
Article and author information
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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.

Data availability

Sequencing data have been deposited in GEO under accession code GSE134173.All data generated or analyzed during this study are included in the manuscript and supporting files.Figure 1C: Table S2Figure 2D: Table S3Figure 4F: Table S4Figure 7C: Table S6

The following data sets were generated

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(2019) Systematic identification of cancer cell vulnerabilities to natural killer cell-mediated immune surveillance
NCBI Gene Expression Omnibus, GSE134173.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE134173

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Article and author information

Author details

Matthew Pech

Department of Oncology, Calico Life Sciences LLC, South San Francisco, United States

Competing interests
Matthew Pech, employee of Calico Life Sciences, LLC.

"This ORCID iD identifies the author of this article:" 0000-0002-1451-0234
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.
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.
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.
Samir Kharbanda

Department of Oncology, Calico Life Sciences LLC, South San Francisco, United States

Competing interests
Samir Kharbanda, employee of Calico Life Sciences, LLC.
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.

"This ORCID iD identifies the author of this article:" 0000-0001-9660-4797
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.
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.
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.

"This ORCID iD identifies the author of this article:" 0000-0001-9033-4028
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.

"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.

Copyright

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.