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Knocking out BATF improves CAR-T cell efficacy by resisting exhaustion and forming central memory cells

ABSTRACT: Knocking out BATF improves CAR-T cell efficacy by resisting exhaustion and forming central memory cells

PROVIDER: PRJNA888383 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21845400_1.fastq.gz	Fastqsanger.gz
	SRR21845400_2.fastq.gz	Fastqsanger.gz
	SRR21845401_1.fastq.gz	Fastqsanger.gz
	SRR21845401_2.fastq.gz	Fastqsanger.gz
	SRR21845402_1.fastq.gz	Fastqsanger.gz

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Knocking out BATF improves CAR-T cell efficacy by resisting exhaustion and forming central memory cells

Project description:Chimeric antigen receptor modified T (CAR-T) cell therapy has limited efficacy against solid tumor, one major challenge is T cell exhaustion. To address this challenge, we performed a candidate gene screen using a hypofunction CAR-T cell model, and found that knocking out BATF improved the performance of CAR-T cells. In different types of CAR-T cells and mouse OT-1 cells, knocking out BATF endows T cells with improved resistance to exhaustion and better tumor eradication efficacy. We find that BATF binds to and up-regulates a subset of exhaustion genes in human CAR-T cells. Furthermore, BATF regulates the expression of genes involved in the development of effector and memory cells, and knocking out BATF shifts the population towards more central memory subset. Therefore, we conclude that BATF is a key factor limiting CAR-T cell function, and its depletion improves CAR-T cells efficacy against solid tumor.

2022-10-12 | GSE215086 | GEO

Project description:Knocking out BATF improves CAR-T cell efficacy by resisting exhaustion and forming central memory cells

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BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (ATAC-seq)

Project description:Cooperative interactions among transcription factors are essential for gene transcription. We previously showed that NFAT and AP-1 (Fos-Jun) transcription factors cooperate to promote the effector functions of T cells, but that under conditions where it is unable to cooperate with AP-1, NFAT imposes a negative feedback programme of T cell hyporesponsiveness (“exhaustion”). Here we show that BATF and IRF4 cooperate to counter T cell exhaustion. Overexpression of Batf in CD8+ 42 T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumour-infiltrating CAR T cells, increased their production of effector cytokines, decreased their expression of inhibitory receptors and the exhaustion-associated transcription factor TOX, and led to the generation of long-lived memory T cells that controlled tumour recurrence. These responses were dependent on the BATF-IRF interaction, since cells expressing a Batf mutant unable to interact with Irf4 did not survive in tumours and did not effectively delay tumour growth. We suggest that BATF overexpression is a therapeutically viable option for improving the anti-tumour responses of CAR TILs, by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.

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BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (RNA-seq)

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BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (ChIP-seq)

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BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells

Project description:BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells

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BATF knockout B cells

Project description:compare wild type and Batf-/- B cells activated for 0 1 or 2 days in vitro. WT or Batf deficient B cells were activated in vitro with LPS for 1 or 2 days, or left untreated. B cells were purified by MACS and activated, harvested and prepped for affymetrix gene expression profiling.

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BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (ChIP-seq)

Project description:BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (ChIP-seq)

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Project description:BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (RNA-seq)

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BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (ATAC-seq)

Project description:BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (ATAC-seq)

| PRJNA647372 | ENA