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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [scATAC-seq scRNA-seq]

ABSTRACT: Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [scATAC-seq scRNA-seq]

PROVIDER: PRJNA1091882 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28456646_1.fastq.gz	Fastqsanger.gz
	SRR28456646_2.fastq.gz	Fastqsanger.gz
	SRR28456647_1.fastq.gz	Fastqsanger.gz
	SRR28456647_2.fastq.gz	Fastqsanger.gz
	SRR28456648_1.fastq.gz	Fastqsanger.gz

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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway

Project description:Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway

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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [ChIP-Seq]

Project description:T-cell exhaustion (Tex) phenotype has limited the efficacy of single-agent immune checkpoint blockade (ICB) in cancer immunotherapy, underscoring the need to target upstream pathways. Clinical trials have indicated that CXCR4 antagonists enhance anti-cancer activity. However, the specific mechanisms through which CXCR4 contributes to immune cell phenotypes are not fully understood. By targeting CXCR4 using antagonists or transgenic mice (Cxcr4flox/flox LckCre), we effectively attenuated the Tex phenotype and enhanced the functional T-cell phenotype in vivo. Additionally, single-cell RNA/TCR-seq analyses demonstrated that CXCR4 inhibition promotes anti-PD-1 immunotherapy by reducing CD8+ Tex phenotype and enriching the abundance of TCR clonotypes in vivo. Mechanically, we found that CXCR4-blocking T cells mitigate Tex phenotype by regulating the JAK2-STAT3 pathway, reducing the interaction between p-STAT3 and TOX. Single-cell ATAC/RNA-seq validated that CXCR4 deficiency epigenetically orchestrates the transition from functional to exhausted phenotypes in CD8+ T cells. Altogether, we demonstrate a mechanism of targeting CXCR4 to orchestrate CD8+ Tex cells in cancers and provide a rationale for the combined CXCR4 antagonists and ICBs in clinical trials.

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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [scATAC-seq; scRNA-seq]

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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [scRNA_VDJ-seq]

Project description:Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [scRNA_VDJ-seq]

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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [RNA-Seq]

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CXCR4 orchestrates the TOX-programmed exhausted phenotype of CD8<sup>+</sup> T cells via JAK2/STAT3 pathway.

Project description:Evidence from clinical trials suggests that CXCR4 antagonists enhance immunotherapy effectiveness in several cancers. However, the specific mechanisms through which CXCR4 contributes to immune cell phenotypes are not fully understood. Here, we employed single-cell transcriptomic analysis and identified CXCR4 as a marker gene in T cells, with CD8+PD-1high exhausted T (Tex) cells exhibiting high CXCR4 expression. By blocking CXCR4, the Tex phenotype was attenuated in vivo. Mechanistically, CXCR4-blocking T cells mitigated the Tex phenotype by regulating the JAK2-STAT3 pathway. Single-cell RNA/TCR/ATAC-seq confirmed that Cxcr4-deficient CD8+ T cells epigenetically mitigated the transition from functional to exhausted phenotypes. Notably, clinical sample analysis revealed that CXCR4+CD8+ T cells showed higher expression in patients with a non-complete pathological response. Collectively, these findings demonstrate the mechanism by which CXCR4 orchestrates CD8+ Tex cells and provide a rationale for combining CXCR4 antagonists with immunotherapy in clinical trials.

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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway

Project description:This SuperSeries is composed of the SubSeries listed below.

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