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In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target

Author

Listed:
  • Robert T. Manguso

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Hans W. Pope

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Margaret D. Zimmer

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Flavian D. Brown

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Kathleen B. Yates

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Brian C. Miller

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology
    Dana-Farber Cancer Institute)

  • Natalie B. Collins

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology
    Children’s Hospital)

  • Kevin Bi

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Martin W. LaFleur

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Vikram R. Juneja

    (Harvard Medical School)

  • Sarah A. Weiss

    (Dana-Farber Cancer Institute)

  • Jennifer Lo

    (Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School)

  • David E. Fisher

    (Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School)

  • Diana Miao

    (Harvard Medical School
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Eliezer Van Allen

    (Harvard Medical School
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • David E. Root

    (Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Arlene H. Sharpe

    (Children’s Hospital
    Evergrande Center for Immunologic Diseases, Harvard Medical School)

  • John G. Doench

    (Broad Institute of Harvard and Massachusetts Institute of Technology)

  • W. Nicholas Haining

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology
    Children’s Hospital)

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.

Suggested Citation

  • Robert T. Manguso & Hans W. Pope & Margaret D. Zimmer & Flavian D. Brown & Kathleen B. Yates & Brian C. Miller & Natalie B. Collins & Kevin Bi & Martin W. LaFleur & Vikram R. Juneja & Sarah A. Weiss &, 2017. "In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target," Nature, Nature, vol. 547(7664), pages 413-418, July.
  • Handle: RePEc:nat:nature:v:547:y:2017:i:7664:d:10.1038_nature23270
    DOI: 10.1038/nature23270
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    2. Irineos Papakyriacou & Ginte Kutkaite & Marta Rúbies Bedós & Divya Nagarajan & Liam P. Alford & Michael P. Menden & Yumeng Mao, 2024. "Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Nina Frey & Luigi Tortola & David Egli & Sharan Janjuha & Tanja Rothgangl & Kim Fabiano Marquart & Franziska Ampenberger & Manfred Kopf & Gerald Schwank, 2022. "Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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    5. Louise A. Baldwin & Nenad Bartonicek & Jessica Yang & Sunny Z. Wu & Niantao Deng & Daniel L. Roden & Chia-Ling Chan & Ghamdan Al-Eryani & Damien J. Zanker & Belinda S. Parker & Alexander Swarbrick & S, 2022. "DNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and immunotherapy response," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Christos Miliotis & Yuling Ma & Xanthi-Lida Katopodi & Dimitra Karagkouni & Eleni Kanata & Kaia Mattioli & Nikolas Kalavros & Yered H. Pita-Juárez & Felipe Batalini & Varune R. Ramnarine & Shivani Nan, 2024. "Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Dario Zimmerli & Chiara S. Brambillasca & Francien Talens & Jinhyuk Bhin & Renske Linstra & Lou Romanens & Arkajyoti Bhattacharya & Stacey E. P. Joosten & Ana Moises Silva & Nuno Padrao & Max D. Welle, 2022. "MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    8. Hanhan Ning & Shan Huang & Yang Lei & Renyong Zhi & Han Yan & Jiaxing Jin & Zhenyu Hu & Kaimin Guo & Jinhua Liu & Jie Yang & Zhe Liu & Yi Ba & Xin Gao & Deqing Hu, 2022. "Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    9. Julia Joung & Paul C. Kirchgatterer & Ankita Singh & Jang H. Cho & Suchita P. Nety & Rebecca C. Larson & Rhiannon K. Macrae & Rebecca Deasy & Yuen-Yi Tseng & Marcela V. Maus & Feng Zhang, 2022. "CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    10. Yazhong Cui & Yang Miao & Longzhi Cao & Lifang Guo & Yue Cui & Chuanzhe Yan & Zhi Zeng & Mo Xu & Ting Han, 2023. "Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    11. Austin M. Gabel & Andrea E. Belleville & James D. Thomas & Siegen A. McKellar & Taylor R. Nicholas & Toshihiro Banjo & Edie I. Crosse & Robert K. Bradley, 2024. "Multiplexed screening reveals how cancer-specific alternative polyadenylation shapes tumor growth in vivo," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    12. Tian-Yu Song & Min Long & Hai-Xin Zhao & Miao-Wen Zou & Hong-Jie Fan & Yang Liu & Chen-Lu Geng & Min-Fang Song & Yu-Feng Liu & Jun-Yi Chen & Yu-Lin Yang & Wen-Rong Zhou & Da-Wei Huang & Bo Peng & Zhen, 2021. "Tumor evolution selectively inactivates the core microRNA machinery for immune evasion," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    13. Shuwei Liang & Eric Tran & Xin Du & Jiajun Dong & Harrison Sudholz & Hao Chen & Zihan Qu & Nicholas D. Huntington & Jeffrey J. Babon & Nadia J. Kershaw & Zhong-Yin Zhang & Jonathan B. Baell & Florian , 2023. "A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-27, December.
    14. Azucena Ramos & Catherine E. Koch & Yunpeng Liu-Lupo & Riley D. Hellinger & Taeyoon Kyung & Keene L. Abbott & Julia Fröse & Daniel Goulet & Khloe S. Gordon & Keith P. Eidell & Paul Leclerc & Charles A, 2023. "Leukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    15. Martin Lauss & Bengt Phung & Troels Holz Borch & Katja Harbst & Kamila Kaminska & Anna Ebbesson & Ingrid Hedenfalk & Joan Yuan & Kari Nielsen & Christian Ingvar & Ana Carneiro & Karolin Isaksson & Kri, 2024. "Molecular patterns of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    16. Georgi Apriamashvili & David W. Vredevoogd & Oscar Krijgsman & Onno B. Bleijerveld & Maarten A. Ligtenberg & Beaunelle Bruijn & Julia Boshuizen & Joleen J. H. Traets & Daniela D’Empaire Altimari & Ale, 2022. "Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    17. John P. Finnigan & Jenna H. Newman & Yury Patskovsky & Larysa Patskovska & Andrew S. Ishizuka & Geoffrey M. Lynn & Robert A. Seder & Michelle Krogsgaard & Nina Bhardwaj, 2024. "Structural basis for self-discrimination by neoantigen-specific TCRs," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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