Systematic identification of cancer cell vulnerabilities to natural killer cell-mediated immune surveillance
- Calico Life Sciences LLC, United States
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
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Systematic identification of cancer cell vulnerabilities to natural killer cell-mediated immune surveillanceNCBI Gene Expression Omnibus, GSE134173.
Article and author information
Author details
Jonathon J O'Brien
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
- Stipan Jonjic, University Rijeka, Croatia
Version history
- Received: April 3, 2019
- Accepted: August 2, 2019
- Accepted Manuscript published: August 27, 2019 (version 1)
- Version of Record published: August 28, 2019 (version 2)
- 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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Systematic identification of cancer cell vulnerabilities to natural killer cell-mediated immune surveillance
eLife 8:e47362.
https://doi.org/10.7554/eLife.47362
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