In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target
- PMID: 28723893
- PMCID: PMC5924693
- DOI: 10.1038/nature23270
In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target
Abstract
Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.
Conflict of interest statement
The authors declare no competing financial interests.
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Republished in
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Immunotherapy: Searching in the immune checkpoint black box.Nat Rev Cancer. 2017 Sep;17(9):511. doi: 10.1038/nrc.2017.75. Epub 2017 Aug 24. Nat Rev Cancer. 2017. PMID: 28835721 No abstract available.
Comment in
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Cancer immunotherapy: Searching in the immune checkpoint black box.Nat Rev Drug Discov. 2017 Sep;16(9):599. doi: 10.1038/nrd.2017.163. Epub 2017 Aug 11. Nat Rev Drug Discov. 2017. PMID: 28799544 No abstract available.
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PTPN2: a tumor suppressor you want deleted?Immunol Cell Biol. 2017 Nov;95(10):859-861. doi: 10.1038/icb.2017.70. Epub 2017 Oct 10. Immunol Cell Biol. 2017. PMID: 28994418 No abstract available.
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CRISPR takes genetic screens forward.Lab Anim (NY). 2020 Jan;49(1):13-16. doi: 10.1038/s41684-019-0445-0. Lab Anim (NY). 2020. PMID: 31853027 No abstract available.
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