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A CRISPR-Cas9 delivery system for in vivo screening of genes in the immune system

Author

Listed:
  • Martin W. LaFleur

    (Harvard Medical School
    Dana-Farber Cancer Institute
    Harvard Medical School and Brigham and Women’s Hospital)

  • Thao H. Nguyen

    (Harvard Medical School
    Harvard Medical School and Brigham and Women’s Hospital)

  • Matthew A. Coxe

    (Harvard Medical School
    Harvard Medical School and Brigham and Women’s Hospital)

  • Kathleen B. Yates

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

  • Justin D. Trombley

    (Harvard Medical School
    Harvard Medical School and Brigham and Women’s Hospital)

  • Sarah A. Weiss

    (Dana-Farber Cancer Institute)

  • Flavian D. Brown

    (Harvard Medical School
    Dana-Farber Cancer Institute
    Harvard Medical School and Brigham and Women’s Hospital)

  • Jacob E. Gillis

    (Harvard Medical School
    Harvard Medical School and Brigham and Women’s Hospital)

  • Daniel J. Coxe

    (School of Energy, Matter, and Transport Engineering at Arizona State University)

  • 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)

  • Arlene H. Sharpe

    (Harvard Medical School
    Harvard Medical School and Brigham and Women’s Hospital
    Broad Institute of Harvard and Massachusetts Institute of Technology)

Abstract

Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient and can perturb cell states. Here we describe CHIME: CHimeric IMmune Editing, a CRISPR-Cas9 bone marrow delivery system to rapidly evaluate gene function in innate and adaptive immune cells in vivo without ex vivo manipulation of these mature lineages. This approach enables efficient deletion of genes of interest in major immune lineages without altering their development or function. We use this approach to perform an in vivo pooled genetic screen and identify Ptpn2 as a negative regulator of CD8+ T cell-mediated responses to LCMV Clone 13 viral infection. These findings indicate that this genetic platform can enable rapid target discovery through pooled screening in immune cells in vivo.

Suggested Citation

  • Martin W. LaFleur & Thao H. Nguyen & Matthew A. Coxe & Kathleen B. Yates & Justin D. Trombley & Sarah A. Weiss & Flavian D. Brown & Jacob E. Gillis & Daniel J. Coxe & John G. Doench & W. Nicholas Hain, 2019. "A CRISPR-Cas9 delivery system for in vivo screening of genes in the immune system," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09656-2
    DOI: 10.1038/s41467-019-09656-2
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    Cited by:

    1. Lawrence M Agius, 2019. "Re-Formulated Immuno-Editing as Agonist and Permissive Elements in Establishment of Foci of Carcinogenesis," Cancer Therapy & Oncology International Journal, Juniper Publishers Inc., vol. 14(1), pages 3-5, May.
    2. Bonnie Huang & James D. Phelan & Silvia Preite & Julio Gomez-Rodriguez & Kristoffer H. Johansen & Hirofumi Shibata & Arthur L. Shaffer & Qin Xu & Brendan Jeffrey & Martha Kirby & Stacie Anderson & Yan, 2022. "In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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