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Nature DOI:10.1038/nature23270

In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target.

Publication TypeJournal Article
Year of Publication2017
AuthorsManguso, RT, Pope, HW, Zimmer, MD, Brown, FD, Yates, KB, Miller, BC, Collins, NB, Bi, K, LaFleur, MW, Juneja, VR, Weiss, SA, Lo, J, Fisher, DE, Miao, D, Van Allen, E, Root, DE, Sharpe, AH, Doench, JG, W Haining, N
JournalNature
Volume547
Issue7664
Pages413-418
Date Published2017 07 27
ISSN1476-4687
KeywordsAnimals, Antigen Presentation, CRISPR-Cas Systems, Gene Editing, Genomics, Humans, Immunotherapy, Interferons, Loss of Function Mutation, Melanoma, Experimental, Mice, NF-kappa B, Protein Tyrosine Phosphatase, Non-Receptor Type 2, T-Lymphocytes, Tumor Escape, Unfolded Protein Response, Xenograft Model Antitumor Assays
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.

DOI10.1038/nature23270
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28723893?dopt=Abstract

Alternate JournalNature
PubMed ID28723893
PubMed Central IDPMC5924693
Grant ListT32 CA207021 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States