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Ramos, Azucena; Koch, Catherine E; Liu-Lupo, Yunpeng; Hellinger, Riley D; Kyung, Taeyoon; Abbott, Keene L; Fröse, Julia; Goulet, Daniel; Gordon, Khloe S; Eidell, Keith P; Leclerc, Paul; Whittaker, Charles A; Larson, Rebecca C; Muscato, Audrey J; Yates, Kathleen B; Dubrot, Juan; Doench, John G; Regev, Aviv; Vander Heiden, Matthew G; Maus, Marcela V; Manguso, Robert T; Birnbaum, Michael E; Hemann, Michael T
Nature communications, 2023-Dec-05, Letnik: 14, Številka: 1Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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