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Status |
Public on Oct 31, 2023 |
Title |
Leukemia-intrinsic determinants of CAR-T response revealed by in vivo genome-wide CRISPR screening [scRNA-seq] |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
CAR-T cells are a promising new treatment for B cell malignancies. However, the majority of patients inevitably go on to experience disease relapse through largely unknown means. To investigate leukemia-intrinsic CAR-T resistance mechanisms, we performed genome-wide CRISPR-Cas9 loss-of-function screening in an immunocompetent murine model of B cell acute lymphoblastic leukemia (B-ALL). We identified IFN𝝲/JAK/STAT signaling and components of the antigen processing and presentation pathway as key mediators of resistance to anti-CD19 CAR-T therapy in vivo, but not in vitro. Transcriptional characterization of this model demonstrated an upregulation of these pathways in CAR-T treated relapsed tumors, and examination of data from CAR-T treated B-ALL patients revealed an association between poor outcomes and increased expression of JAK/STAT/MHC-I in leukemia cells. Together, our data identify an unexpected mechanism of resistance to immunotherapy, in which tumor cell interaction with IFN𝝲-secreting CAR-T cells in vivo activates the expression of an MHC-I inhibitory T cell program.
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Overall design |
Single cell RNAseq comparison of 3 biological replicates each of mouse B-ALL cells isolated from either spleen or bone marrow challenged with CAR-T cells targeting either CD19 or a EGFRvIII
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Contributor(s) |
Ramos A, Koch C, Liu Y, Hellinger RD, Kyung T, Larson RC, Fröse J, Goulet D, Doench JG, Regev A, Maus MV, Birnbaum ME, Hemann MT |
Citation(s) |
38052854 |
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Submission date |
Feb 04, 2022 |
Last update date |
Dec 14, 2023 |
Contact name |
Charles Arthur Whittaker |
E-mail(s) |
charliew@mit.edu
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Organization name |
Koch Institute
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Street address |
77 Mass Ave 76-189
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City |
Cambridge |
State/province |
MA |
ZIP/Postal code |
02152 |
Country |
USA |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (12)
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This SubSeries is part of SuperSeries: |
GSE196143 |
Leukemia-intrinsic determinants of CAR-T response revealed by in vivo genome-wide CRISPR screening |
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Relations |
BioProject |
PRJNA803465 |