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HDACi-dependent microenvironmental normalization overcomes tumor burden-induced T-cell exhaustion [RNA-seq]

ABSTRACT: HDACi-dependent microenvironmental normalization overcomes tumor burden-induced T-cell exhaustion [RNA-seq]

PROVIDER: PRJNA998403 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25420500.fastq.gz	Fastqsanger.gz
	SRR25420501.fastq.gz	Fastqsanger.gz
	SRR25420502.fastq.gz	Fastqsanger.gz
	SRR25420503.fastq.gz	Fastqsanger.gz
	SRR25420504.fastq.gz	Fastqsanger.gz

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Project description:Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. While immune checkpoint blockade and adoptive T cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden-related pathway changes that are conducive to T-cell exhaustion. We then determined if microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. Experimental Design: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor (HDACi) MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. Results: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively up-regulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2-STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed towards terminal effector cell-like CD44+ Tim-3hi TCF1- CD127- KLRG1+ differentiation. Conclusion: Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation. We used whole transcriptome arrays (Clariom D) to determine the effect of MS-275 on exhausted T cells in ACT+/-MS-275-treated mice

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HDACi-dependent microenvironmental normalization overcomes tumor burden-induced T-cell exhaustion [RNA-seq]

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