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Paired CRISPR screens to map gene regulation in cis and trans (HiChIP)

ABSTRACT: In this study, we develop a scalable approach that pairs discovery of cis- and trans-acting elements to systematically decipher the gene regulatory network. We explore the regulation of the immune checkpoint PD-L1 under both basal and IFNγ-stimulated contexts. PD-L1 expression on tumor cells serves as a clinically-actionable diagnostic for immune checkpoint blockade therapy across multiple cancer types.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255700 | GEO | 2024/11/28

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE255700_BXPC3_HiChIP_NoIFNy_5kbBin.contacts.txt.gz	Txt
	GSE255700_BXPC3_HiChIP_PlusIFNy_5kbBin.contacts.txt.gz	Txt
	GSE255700_RAW.tar	Raw
	filelist.txt	Txt

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Paired CRISPR screens to map gene regulation in cis and trans (CUT&RUN)

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Project description:Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.

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