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

Author:

Pech Matthew F1ORCID,Fong Linda E1,Villalta Jacqueline E1,Chan Leanne JG1,Kharbanda Samir1,O'Brien Jonathon J1ORCID,McAllister Fiona E1,Firestone Ari J1,Jan Calvin H1ORCID,Settleman Jeffrey1ORCID

Affiliation:

1. Calico Life Sciences LLC, South San Francisco, 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-γ 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.

Funder

Calico Life Sciences LLC

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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