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

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. Whittaker, Rebecca C. Larson, Audrey J. Muscato, Kathleen B. Yates, Juan Dubrot, John G. Doench, Aviv Regev, Matthew G. Heiden, Marcela V. Maus, Robert T. Manguso, Michael E. Birnbaum and Michael T. Hemann ()
Additional contact information
Azucena Ramos: Massachusetts Institute of Technology
Catherine E. Koch: Massachusetts Institute of Technology
Yunpeng Liu-Lupo: Massachusetts Institute of Technology
Riley D. Hellinger: Massachusetts Institute of Technology
Taeyoon Kyung: Massachusetts Institute of Technology
Keene L. Abbott: Massachusetts Institute of Technology
Julia Fröse: Massachusetts Institute of Technology
Daniel Goulet: Massachusetts Institute of Technology
Khloe S. Gordon: 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
Audrey J. Muscato: Massachusetts General Hospital
Kathleen B. Yates: Massachusetts General Hospital
Juan Dubrot: Massachusetts General Hospital
John G. Doench: Broad Institute of Harvard and Massachusetts Institute of Technology
Aviv Regev: Massachusetts Institute of Technology
Matthew G. Heiden: Massachusetts Institute of Technology
Marcela V. Maus: Massachusetts General Hospital
Robert T. Manguso: Harvard Medical School
Michael E. Birnbaum: Massachusetts Institute of Technology
Michael T. Hemann: Massachusetts Institute of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43790-2

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