Leukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening
Year: 2023
Type: article
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.
Source: Nature Communications
Authors: 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. Vander Heiden, Marcela V. Maus, Robert T. Manguso, Michael E. Birnbaum, Michael T. Hemann
Institutions: Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, Harvard University, Massachusetts General Hospital, Broad Institute, Centro de Investigación Médica Aplicada, Universidad de Navarra, Howard Hughes Medical Institute, Klarman Cell Observatory, Dana-Farber Cancer Institute, Ragon Institute of MGH, MIT and Harvard
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: U.S. Department of Health and Human Services, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, National Institutes of Health, Ludwig Center at Harvard, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: Identifying and targeting evolutionary trajectories in cancer, G2360436881, Dissecting the mechanism of cyclophosphamide-enhanced antibody efficacy, Medical Scientist Training Program, G3750322928, Training in Transplantation Biology, G4774430914, G6879439366, RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies, Cancer Center Support (Core) Grant, Medical Scientist Training Program, Understanding the role of metabolism in cancer
OpenAlex ID: W4389334320