In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target

By R. Manguso, Hans W. Pope, Margaret D. Zimmer, Flavian D. Brown, Kathleen B. Yates, Brian C. Miller, Natalie B Collins, K. Bi, M. LaFleur, Vikram R. Juneja and 9 more. Nature, 2017

989 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/68f74ee160d79d6d29dd0cc3bd19616aab271a90

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Citations in the corpus

Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells (2018, positive): “…observed in Merkel cell carcinoma (Paulson et al., 2018) and in an in vivo CRISPR screening program that identified Qa-1b (the mouse HLA-E ortholog) as a cancer immunotherapy target, because Qa-1b loss-of-function increased the efficacy of immunotherapy by PD-1 blockade (Manguso et al., 2017).”
Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “demonstrated activating mutations in the tyrosine-protein phosphatase nonreceptor type 2 (Ptpn2), which negatively regulates JAK1 and JAK2, contributes to resistance to ICIs through IFN-γ resistance (Manguso et al., 2017).”
Genomic features of response to combination immunotherapy in patients with advanced non-small cell lung cancer (2018, background): “, 2016) and pre-clinical reports usingCRISPR/Cas9 screening (Burr et al., 2017;Manguso et al., 2017; Patel et al., 2017) have begun to elucidate genes in both tumors and T cells that are critical to response or resistance to immunotherapy.”
Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “…in JAK1/2 as an innate and acquired resistance mechanism, in vivo CRISPR screening using a mouse model of melanoma demonstrated that deletion of IFNg receptors (Ifrngr1 and Ifngr2) and JAK/STAT pathway components (Jak1, Jak2, and Stat1) resulted in resistance to PD-1 blockade (Manguso et al, 2017).”