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August 3, 2017 - 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 signaling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signaling, 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.
My Takeaways:
1. The potential of immunotherapy has been proven highly effective in animal models over and over again, however, transition to its efficacy in humans has been limited with little to no understanding of why. The researchers use CRISPR gene editing, along with various other biological techniques, to tease out a specific protein that is interfering with immune therapy. The scientists identify a single target, PTPN2, that caused significant changes in the efficacy of standard immunotherapy treatment regimes.
2. A company can easily be built around the translation of a therapeutic to block production of this Ptpn2 protein. The hurdles will be in the identification of such therapeutic, it’s safety profile, and the really big hurdle will be the proof in human clinical studies. While the researchers seem to identify one protein that’s blocking immunotherapy efficacy, they did not prove that there are other potential roadblocks to immunotherapy success in humans. Therefore, while exciting, the science is still risky.
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By Michael BruckmanAbstract: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 signaling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signaling, 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.
My Takeaways:
1. The potential of immunotherapy has been proven highly effective in animal models over and over again, however, transition to its efficacy in humans has been limited with little to no understanding of why. The researchers use CRISPR gene editing, along with various other biological techniques, to tease out a specific protein that is interfering with immune therapy. The scientists identify a single target, PTPN2, that caused significant changes in the efficacy of standard immunotherapy treatment regimes.
2. A company can easily be built around the translation of a therapeutic to block production of this Ptpn2 protein. The hurdles will be in the identification of such therapeutic, it’s safety profile, and the really big hurdle will be the proof in human clinical studies. While the researchers seem to identify one protein that’s blocking immunotherapy efficacy, they did not prove that there are other potential roadblocks to immunotherapy success in humans. Therefore, while exciting, the science is still risky.