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Ablation of S1PR4 triggers CD8+ T cell expansion to reduce tumor growth and improve therapy

ABSTRACT: Ablation of S1PR4 triggers CD8+ T cell expansion to reduce tumor growth and improve therapy

PROVIDER: PRJNA638131 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11955132.fastq.gz	Fastqsanger.gz
	SRR11955133.fastq.gz	Fastqsanger.gz
	SRR11955134.fastq.gz	Fastqsanger.gz
	SRR11955135.fastq.gz	Fastqsanger.gz
	SRR11955136.fastq.gz	Fastqsanger.gz

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Ablation of S1PR4 triggers CD8+ T cell expansion to reduce tumor growth and improve therapy

Project description:We studied the role of S1PR4 on tumor progression using the PyMT mammary carcinoma mouse model and the AOM/DSS model for colitis-associated cancer. To gain insights of the underlying mechanism how S1PR4 ablation resulted in enhanced intratumoral CD8+ T cell abundance, we performed whole transcriptome profiling of total WT and S1PR4 KO colons subjected to the AOM/DSS model (day 84) as well as FACS-sorted CD8+ T cells from WT and S1PR4 KO tumors of PyMT mice. Next-generation mRNA sequencing, in triplicates, on a NextSeq 500 (PyMT CD8+ T cells) or a HiSeq 2000 (AOM/DSS model) high-throughput sequencer was used.

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Project description:Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) is effective in treating PD-1 refractory melanoma, but requires adequate ex vivo expansion of TIL. Methods: CD4+ and CD8+ TIL from metastatic melanoma patients treated with TIL ACT were analyzed by RNA-seq (n=12) and ChIP-seq of acetylated histone 3 (n=19). Patients were grouped into “TIL high” and “TIL low” based on division at the median number of TIL infused. The number of TIL infused and CD4+ TIL frequency were correlated with overall survival (OS). Results: The number of TIL infused correlated with longer OS (R2=0.57, p=0.00076), and the percent of CD4+ infused was negatively correlated with the total number of TIL infused (R2=0.64, p=0.00047). RNA-seq analysis of CD4+ TIL showed increases in Th2/Th17/Treg transcripts and pathways in the TIL low group. ChIP-seq analysis of CD8+ TIL showed decreased acetylation in the TIL low group in genes upregulated during CD8+ activation. Conclusion: The numbers of TIL infused were associated with increased overall survival, while RNA-seq suggested that polarized CD4+ cells in the transferred TIL were associated with decreased overall expansion. These data suggest that improper CD4+ TIL polarization may reduce expansion and treatment efficacy.

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