Dataset Information

PRMT7-specific PROTAC degrader achieves improved adoptive cancer immunotherapy by enhancing CD8+ T effector function through NF-kB activation.

ABSTRACT: New therapeutics are required to ameliorate cytotoxic T lymphocytes (CTL) for improved immunotherapy and T cell therapies. Herein we report that deletion of Prmt7 in T cells in mice with CD4-Cre increased CD8+ T effector cell cytokine production, cytolytic activity and anti-tumor activity of CTLs by transcriptional reprogramming. We show that Prmt7-deficiency in CTLs reprograms the CD8+ T cells with many transcription factors allowing them to exhibit increased proliferation, and express effector molecules. To translate these findings into a potential clinically applicable treatment, we generated a PRMT7 PROTAC degrader (MS54). We show that CTLs treated with the MS54 had similar reprogramming as the Prmt7 cKO CTLs. Adoptive cell transfer of MS54-treated CTLs from OT-I mice significantly enhanced their anti-tumor activity in a syngeneic melanoma murine cancer model. Human CTLs treated with the MS54 had increased proliferation, and enhanced activation markers. Our findings show that the MS54 has potential therapeutic utility for immunotherapy and adoptive cell therapy by reprogramming CTLs.

ORGANISM(S): Mus musculus

PROVIDER: GSE309747 | GEO | 2026/07/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Purpose: RNA-sequencing analysis defined a novel role for PRMT7 in melanoma cancer immunotherapy. Methods: PRMT7-deficient cells and control B16.F10 cells treated with mIFN-γ (100ng/ml) for 24 hours. B16.F10 melanoma cells mRNA profiles were generated by deep sequencing, in triplicate using TruSeq Stranded mRNA Sample Prep Kit with TruSeq Unique Dual Indexes (Illumina, Hiseq4000, SR75 platform located at San Diego, CA; UCSD IGM Genomics Facility, La Jolla, CA). Resulting libraries were multiplexed and sequenced with 100 base pair (bp) to a depth of approximately 30 million reads per sample. The sequence reads that passed quality filters were trimmed with Trimmomatic v0.39. STAR v2.7.1a was then used to align the reads to the mouse genome (mm10/GRCm38). Gene expression was quantified across all samples with HOMER v4.11.1, and the normalization was carried out through the regularized logarithm (rlog) transformation of DESeq2 v1.26.0. Differential expression between PRMT7 WT and knockdown samples were calculated through DESeq2 v1.26.0, and the gene expression was considered significantly different if the absolute value of the log-fold-change (LFC) was higher than 2, the base means larger than 10 and the false discovery rate (FDR) less than 0.05. Results: Differential expression analysis between the siLuc and siPRMT7 conditions yielded 185 and 251 genes with statistically significant differences and absolute fold change greater than 2 in the IFN– and IFN+ treatments respectively. Of these, 85% of genes are upregulated in the IFN– treatment, while 72% of genes are downregulated in the IFN+ treatment. Gene ontology analysis using the 185 and 251 lists of differentially expressed genes implies that the downregulated biological processes are enriched for the immune response pathways, while upregulated genes are more involved in the cell cycle process. Altered expression of some genes was confirmed with qRT–PCR, demonstrating the high degree of sensitivity of the RNA-seq method. Hierarchical clustering of differentially expressed genes uncovered several as yet uncharacterized genes that may contribute to better understand PRMT7 function in cancer immunotherapy. Conclusions: Our study represents the first detailed analysis of B16.F10 melanoma transcriptomes without PRMT7 expression, with biologic replicates, generated by RNA-seq technology. We conclude that RNA-seq based transcriptome characterization would expedite genetic network analyses and permit the dissection of PRMT7 biologic functions in modulating melanoma transcriptome.

Dataset Information

PRMT7-specific PROTAC degrader achieves improved adoptive cancer immunotherapy by enhancing CD8+ T effector function through NF-kB activation.

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets