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Schlafen 5 (SLFN5) is an Intracellular Immune Checkpoint and controls Interferon (IFN) Responses in Pancreatic Ductal Adenocarcinoma (PDAC)

ABSTRACT: We provide evidence that human and murine SLFN5 proteins are modulators of Type I IFN responses and the immune response in pancreatic cancer. Blocking expression of Slfn5 in PDAC enhances IFN-responses, suppresses tumor growth, and prolongs survival in immunocompetent mice. Notably, immunophenotypic analysis reveals a reduction in tumor-associated myeloid cells (TAMCs) alongside an increase in tumor infiltrating effector cells in tumors. These findings implicate SLFN5 acts as an intracellular immune checkpoint and identify it as a unique therapeutic target for the development of novel therapies for PDAC and possibly other malignancies

ORGANISM(S): Homo sapiens

PROVIDER: GSE282985 | GEO | 2026/01/14

REPOSITORIES: GEO

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Schlafen 5 (SLFN5) is an Intracellular Immune Checkpoint and controls Interferon (IFN) Responses in Pancreatic Ductal Adenocarcinoma (PDAC)

Project description:Schlafen 5 (SLFN5) is an Intracellular Immune Checkpoint and controls Interferon (IFN) Responses in Pancreatic Ductal Adenocarcinoma (PDAC)

| PRJNA1191415 | ENA

Schlafen 5 as a Novel Therapeutic Target in Pancreatic Ductal Adenocarcinoma

Project description:We provide evidence that a member of the human Schlafen (SLFN) family of proteins, SLFN5, is overexpressed in human pancreatic ductal adenocarcinoma (PDAC). Targeted deletion of SLFN5 results in decreased PDAC cell proliferation and suppresses PDAC tumorigenesis in in vivo PDAC models. Importantly, high expression levels of SLFN5 correlate with worse outcomes in PDAC patients, implicating SLFN5 in the pathophysiology of PDAC that leads to poor outcomes. Our studies establish novel regulatory effects of SLFN5 on cell cycle progression through binding/blocking of the transcriptional repressor E2F7, promoting transcription of key genes that stimulate S phase progression. Together, our studies suggest an essential role for SLFN5 in PDAC and support the potential for developing new therapeutic approaches for the treatment of pancreatic cancer through SLFN5 targeting.

2021-04-14 | PXD021749 | Pride

Regulatory Role of SLFN5 in Type I Interferon Signaling

Project description:We provide evidence that a member of the IFN-regulated member of the Schlafen (SLFN) family of proteins, SLFN5, promotes the malignant phenotype in glioblastoma multiforme (GBM). Our studies demonstrate that SLFN5 negatively regulates expression of key interferon stimulated genes (ISGs) that mediate important biological functions, including anti-viral and antineoplastic responses.

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RNA-seq of two Pancreatic ductal adenocarcinoma (PDAC) cell lines BxPC-3 and PANC-1 treated with 3x8 Gy X-rays without or with the PARP7 inhibitors RBN-2397 and KMR-206

Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and is associated with a dismal prognosis. Due to late diagnosis, the disease is frequently locally advanced and not amenable to surgical resection, and only a small fraction of patients benefit from radio- or chemotherapy. Immunotherapy has shown limited efficacy as monotherapy, largely due to the profoundly immunosuppressive tumor microenvironment. Recent studies have demonstrated that anti-tumor immune responses can be elicited in pancreatic cancer through activation of the cGAS-STING and RIG-I-MAVS pathways, particularly in the context of radiation therapy. Notably, a hypofractionated radiation regimen of 3×8 Gy has been shown to be more effective than a single dose in inducing immunogenic cell death, type I interferon (IFN-I) signaling, and pro-inflammatory cytokine production. PARP7 inhibitors have also been reported to promote anti-tumor immunity by activating IFN-I responses in lung and colon cancer. Here, we show that in PDAC cells, PARP7 inhibition potentiates the effects of radiation by enhancing STING- and NF-κB dependent immunogenic signaling, inflammatory gene expression, pro-inflammatory cytokine release, immunogenic cell death, and immune cell activation. We performed RNA-seq analysis of all two PDAC cell lines treated with 3x8 Gy alone, or in combination with two different PARP7 inhibitors RBN-2397 and KMR-206.

2026-06-01 | E-MTAB-16549 | biostudies-arrayexpress

Human Schlafen 5 (SLFN5) is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma (RCC) Cells

Project description:There is some emerging evidence that members of the Schlafen (SLFN) family of proteins mediate antineoplastic responses, but the mechanisms accounting for these effects are not known. We provide evidence that human SLFN5, an interferon (IFN)- inducible member of the family, exhibits key roles in controlling motility and invasiveness of renal cell carcinoma (RCC) cells. Our studies define the mechanism by which this occurs, demonstrating that SLFN5 negatively controls expression of matrix metalloproteinases (MMP)-1 and -13 and several other genes involved in the control of malignant cell motility. Importantly, our data establish that SLFN5 expression correlates with a better overall survival in a large cohort of patients with RCC. The inverse relationship between SLFN5 expression and RCC aggressiveness raises the possibility of developing unique therapeutic approaches in the treatment of RCC, by modulating SLFN5 expression.

2015-06-01 | GSE64399 | GEO

Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma (PDAC)

Project description:Determine methylation pattern in PDAC a genome-wide analysis was performed in a cohort of 167 PDAC and 29 adjacent pancreatic tissues samples using the Infinium 450k methylation arrays (Illumina). 167 pancreatic tumors (PDAC) x 29 adjacent -non tumor samples.

2014-07-08 | E-GEOD-49149 | biostudies-arrayexpress

Single-cell RNA sequencing reveals Lin28b-dependent immune modulation in the PDAC tumor microenvironment

Project description:Cancer-associated fibroblasts (CAFs) play a crucial role in shaping the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). This study investigates the impact of an RNA-binding protein Lin28b on the immune landscape of PDAC. Single-cell RNA sequencing (scRNA-seq) was performed on orthotopic pancreatic tumors from wild-type (WT) and fibroblast-specific Lin28b knockout (Fsp-Cre;Lin28bfl/fl) mice. Our analysis revealed that Lin28b expression in CAFs promotes an immunosuppressive TME characterized by reduced immune cell infiltration and dampened type I interferon (IFN) signaling. Conversely, Lin28b deletion in CAFs resulted in increased infiltration of immune cells, particularly CD8+ T cells and enhanced cytotoxic T cell activity. These findings identify Lin28b as a CAF-intrinsic molecular brake on anti-tumor immunity and provide a rationale for targeting the Lin28 to overcome PDAC resistance to immunotherapy.

2026-06-21 | GSE306321 | GEO

Bulk RNA-seq analysis of PDAC tumor Cells

Project description:Orthotopic PDAC tumor were established with KPC and KPSC cells, respectively. After about 10-14 days, PDAC cells with Setd2-KO and Setd2-WT were sorted from orthotopic PDAC tumor by DPAI-CD45.2-Pdpn-Epcam+, and used for RNA preparation.

2024-08-07 | GSE196752 | GEO

The CD49b (ITGA2) Collagen Receptor Excludes CD8+ T Cell Infiltration in Pancreatic Ductal Adenocarcinoma (PDAC)

Project description:PDAC is characterized by a dense desmoplastic stroma, contributing to tumor progression and immune evasion. This study investigates the functional role of CD49b in modulating anti-tumor immune responses and collagen architecture in PDAC. CD49b demonstrated a high tumor-specific expression compared to normal pancreatic tissues and peripheral blood mononuclear cells. Loss of CD49b impaired PDAC cell adhesion to collagen, suppressed and delayed the tumor growth, and enhanced CD8+ T cell infiltration. In vivo depletion of CD8 T cells rescued the tumor growth in CD49b knock-out tumors. CD49b-knockout tumors showed increased secretion of CXCL10 chemokine, which drives T cell chemotaxis, while FAK signaling was downregulated. FAK overexpression restored tumor growth. CD49b knockout changed alignment of collagen fibers which was associated with a microenvironment permissive to immune infiltration. Targeting of CD49b with Vatelizumab disrupted PDAC cell adhesion and reduced tumor progression while increasing CD8+ T cells infiltration. CD49b is a key regulator of collagen-mediated immune interactions in PDAC, and these results support its potential as a therapeutic target.

2026-06-01 | GSE331086 | GEO

Single-cell RNA-Sequencing of pancreatic and PDAC stromal cells

Project description:Most cancers including pancreatic ductal adenocarcinoma (PDAC) are infiltrated by PNS neurons participating in their complex tumor microenvironment. However, their cell bodies and nuclei are located in the para- and pre-vertebral PNS ganglia located far from the tumor mass itself. Thus, molecular information on healthy organ- vs. cancer-infiltrating neurons is currently lacking in any sequencing dataset of healthy or tumor tissue. Here, we specifically isolate fibroblasts, immune, endothelial and PDAC cells and subject them to single-cell RNA-Sequencing using the 10x genomics platform.

2025-02-28 | E-MTAB-12906 | biostudies-arrayexpress

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