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Leukemia-intrinsic determinants of CAR-T response revealed by in vivo genome-wide CRISPR screening [scRNA-seq]

ABSTRACT: Leukemia-intrinsic determinants of CAR-T response revealed by in vivo genome-wide CRISPR screening [scRNA-seq]

PROVIDER: PRJNA803465 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17886627_1.fastq.gz	Fastqsanger.gz
	SRR17886627_2.fastq.gz	Fastqsanger.gz
	SRR17886628_1.fastq.gz	Fastqsanger.gz
	SRR17886628_2.fastq.gz	Fastqsanger.gz
	SRR17886629_1.fastq.gz	Fastqsanger.gz

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

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

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Leukemia-intrinsic determinants of CAR-T response revealed by in vivo genome-wide CRISPR screening [scRNA-seq]

Project description: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 IFN /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 IFN -secreting CAR-T cells in vivo activates the expression of an MHC-I inhibitory T cell program.

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CRISPR Screening of CAR T Cells and Cancer Stem Cells Reveals Critical Dependencies for Cell-Based Therapies [GSC]

Project description:Glioblastoma (GBM) is the most prevalent primary malignant brain tumor, containing self-renewing stem-like GBM stem cells (GSCs) that have been a focus of immunotherapies. Chimeric antigen receptor (CAR) T cell therapy has shown evidence of clinical activity, but overall limited responses in patients with GBMs. Here, we interrogated molecular determinants of CAR T cell-mediated GBM killing through whole-genome CRISPR screens in both CAR T cells and patient-derived GSCs. CRISPR screening of CAR T cells identified dependencies for their effector functions, including TLE4 and IKZF2. Targeted knockout of these genes in CAR T cells robustly enhanced antitumor efficacy against GBM patient-derived xenografts (PDXs). Bulk and single cell-RNA sequencing of edited CAR T cells revealed transcriptional profiles of superior effector function and inhibited exhaustion responses. Reciprocal screening of GSCs identified genes essential for their susceptibility to CAR-mediated killing, including RELA and NPLOC4, the knockout of which altered the tumor-immune signaling axis and increased responsiveness of CAR therapy. Overall, CRISPR screening of CAR T cells and GSCs are promising strategies to discover avenues and inform potential combinatorial approaches for enhancing CAR T cell therapeutic efficacy against GBM, and can be extended to reveal key mediators of immunotherapy responses across solid tumors.

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Project description: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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