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Leukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening

Author

Listed:
  • Azucena Ramos

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Catherine E. Koch

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Yunpeng Liu-Lupo

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Riley D. Hellinger

    (Massachusetts Institute of Technology)

  • Taeyoon Kyung

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Keene L. Abbott

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Julia Fröse

    (Massachusetts Institute of Technology)

  • Daniel Goulet

    (Massachusetts Institute of Technology)

  • Khloe S. Gordon

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Keith P. Eidell

    (Massachusetts Institute of Technology)

  • Paul Leclerc

    (Massachusetts Institute of Technology)

  • Charles A. Whittaker

    (Massachusetts Institute of Technology)

  • Rebecca C. Larson

    (Massachusetts General Hospital
    Harvard Medical School)

  • Audrey J. Muscato

    (Massachusetts General Hospital
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Kathleen B. Yates

    (Massachusetts General Hospital
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Juan Dubrot

    (Massachusetts General Hospital
    Broad Institute of Harvard and Massachusetts Institute of Technology
    University of Navarra)

  • John G. Doench

    (Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Aviv Regev

    (Massachusetts Institute of Technology
    Broad Institute of Harvard and Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard
    Howard Hughes Medical Institute)

  • Matthew G. Heiden

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Dana-Farber Cancer Institute)

  • Marcela V. Maus

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

  • Robert T. Manguso

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

  • Michael E. Birnbaum

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Michael T. Hemann

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

Abstract

CAR-T therapy is a promising, novel treatment modality for B-cell malignancies and yet many patients relapse through a variety of means, including loss of CAR-T cells and antigen escape. To investigate leukemia-intrinsic CAR-T resistance mechanisms, we performed genome-wide CRISPR-Cas9 loss-of-function screens in an immunocompetent murine model of B-cell acute lymphoblastic leukemia (B-ALL) utilizing a modular guide RNA library. We identified IFNγR/JAK/STAT signaling and components of antigen processing and presentation pathway as key mediators of resistance to CAR-T therapy in vivo; intriguingly, loss of this pathway yielded the opposite effect in vitro (sensitized leukemia to CAR-T cells). Transcriptional characterization of this model demonstrated upregulation of these pathways in tumors relapsed after CAR-T treatment, and functional studies showed a surprising role for natural killer (NK) cells in engaging this resistance program. Finally, examination of data from B-ALL patients treated with CAR-T revealed an association between poor outcomes and increased expression of JAK/STAT and MHC-I in leukemia cells. Overall, our data identify an unexpected mechanism of resistance to CAR-T therapy in which tumor cell interaction with the in vivo tumor microenvironment, including NK cells, induces expression of an adaptive, therapy-induced, T-cell resistance program in tumor cells.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43790-2
    DOI: 10.1038/s41467-023-43790-2
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    References listed on IDEAS

    as
    1. Keith A. Lawson & Cristovão M. Sousa & Xiaoyu Zhang & Eiru Kim & Rummy Akthar & Joseph J. Caumanns & Yuxi Yao & Nicholas Mikolajewicz & Catherine Ross & Kevin R. Brown & Abdelrahman Abou Zid & Zi Peng, 2020. "Functional genomic landscape of cancer-intrinsic evasion of killing by T cells," Nature, Nature, vol. 586(7827), pages 120-126, October.
    2. 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.
    3. Elad Jacoby & Sang M. Nguyen & Thomas J. Fountaine & Kathryn Welp & Berkley Gryder & Haiying Qin & Yinmeng Yang & Christopher D. Chien & Alix E. Seif & Haiyan Lei & Young K. Song & Javed Khan & Daniel, 2016. "CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity," Nature Communications, Nature, vol. 7(1), pages 1-10, November.
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