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CD137 costimulation counteracts TGFβ inhibition of NK cell anti-tumor function and promotes the acquisition of tissue-resident Th9-like properties [2 treatments]

ABSTRACT: Enhancing NK cell-based cancer immunotherapy by overcoming immunosuppression is an unmet goal. Here, we demonstrate the ability of the anti-CD137 agonist urelumab for overcoming TGF-β-mediated inhibition of human NK-cell proliferation and sustained anti-tumor function. Transcriptomic, immunophenotypic and functional analyses evidenced that CD137 costimulation modified the transcriptional program induced by TGF-β on activated NK cells by limiting SMAD4-dependent inhibition of pro-proliferative (CD25, cMyc), activating (NKG2D, CD16) and effector (Granzyme B, IFNγ) molecules while maintaining SMAD4-independent acquisition of tumor-retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGF-β1 and CD137 agonist showed preserved antibody-dependent cytotoxicity against cancer cells, recovered CCL5 and IFNγ secretion and gained the capacity for producing IL-9 upon restimulation. Treatment of breast tumor-derived multicellular cultures with trastuzumab and urelumab recapitulated CD137 induction and fostered tumor-infiltrating CD16+ NK cell persistence. Our data reveals CD137 as a targetable checkpoint for overturning TGF-β constrains on NK cell anti-tumor responses

ORGANISM(S): Homo sapiens

PROVIDER: GSE156199 | GEO | 2021/09/10

REPOSITORIES: GEO

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CD137 costimulation counteracts TGFβ inhibition of NK cell anti-tumor function and promotes the acquisition of tissue-resident Th9-like properties [4 treatments]

Project description:Enhancing NK cell-based cancer immunotherapy by overcoming immunosuppression is an unmet goal. Here, we demonstrate the ability of the anti-CD137 agonist urelumab for overcoming TGF-β-mediated inhibition of human NK-cell proliferation and sustained anti-tumor function. Transcriptomic, immunophenotypic and functional analyses evidenced that CD137 costimulation modified the transcriptional program induced by TGF-β on activated NK cells by limiting SMAD4-dependent inhibition of pro-proliferative (CD25, cMyc), activating (NKG2D, CD16) and effector (Granzyme B, IFNγ) molecules while maintaining SMAD4-independent acquisition of tumor-retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGF-β1 and CD137 agonist showed preserved antibody-dependent cytotoxicity against cancer cells, recovered CCL5 and IFNγ secretion and gained the capacity for producing IL-9 upon restimulation. Treatment of breast tumor-derived multicellular cultures with trastuzumab and urelumab recapitulated CD137 induction and fostered tumor-infiltrating CD16+ NK cell persistence. Our data reveals CD137 as a targetable checkpoint for overturning TGF-β constrains on NK cell anti-tumor responses.

2021-09-10 | GSE143375 | GEO

TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation [RNAseq]

Project description:SMAD4, a key mediator of TGF-beta signaling, plays a crucial role in T cells to prevent chronic intestinal inflammation through unknown mechanisms. We reveal that SMAD4 in CD8 T cells prevents chronic intestinal inflammation primarily in a TGF-beta-independent manner. Mechanistically, SMAD4, in CD8 T cells, acts as a basal and tonic repressor of TGF-beta-target genes at the transcriptional and epigenetic level, prior to any TGF-beta signal. SMAD4 deletion affects aberrantly a wide range of TGF-beta-target genes, thereby promoting accumulation and epithelial retention of CD8.alpha.beta T cells inversely to total TGF-beta signaling disruption. Moreover, SMAD4 deletion unleashes the expression of TGF-beta-signaling-repressors and hampers TGF-β-mediated CD8 T cell immunosuppression, eliciting their chronic activation. Hence, in a feedforward mechanism, SMAD4 both blocks the TGF-beta signature in CD8 T cells and pre-sensitizes them to TGF-beta.

2022-03-15 | GSE188933 | GEO

TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation [ChIPseq]

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SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4

Project description:The tumor suppressive effects of TGF-β are classically associated with the activation of the “canonical” SMAD-mediated pathway, whereas its oncogenic effects are largely attributed to its “non-canonical signaling”. We herein provide evidence of an oncogenic effect for SMAD2 and 3 in response to TGF-β in SMAD4-null cancer cells. Using the CRISPR/Cas9 technology, we report that simultaneous knockout of Smad2 and 3 in Smad4-negative pancreatic ductal adenocarcinoma (PDAC) cells compromises TGF-β-driven collective migration mediated by FAK and Rho/Rac signaling. Moreover, RNA-sequencing analyses highlight a TGF-β gene signature related to aggressiveness mediated by SMAD2 and 3 in the absence of SMAD4. Using PDAC patients cohorts, we reveal that SMAD4-negative tumors with high levels of (phospho)-SMAD2 are more aggressive and have a poorer prognosis. Thus, loss of SMAD4 tumor suppressive activity in PDAC is associated with oncogenic gain-of-function of SMAD2 and 3 and the onset of associated deleterious effects.

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TGF-β Tumor Suppression Through A Lethal EMT

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Project description:The vertebrate homologues of Drosophila dachsund, DACH1 and DACH2, have been implicated as important regulatory genes in development. DACH1 plays a role in retinal and pituitary precursor cell proliferation and DACH2 plays a specific role in myogenesis. DACH proteins contain a domain (DS-domain) that is conserved with the proto-oncogenes Ski and Sno. Since the Ski/Sno proto-oncogenes repress AP-1 and SMAD signaling, we hypothesized that DACH1 might play a similar cellular function. Herein, DACH1 was found to be expressed in breast cancer cell lines and to inhibit TGF-beta induced apoptosis. DACH1 repressed TGF-beta induction of AP-1 and Smad signaling in gene reporter assays and repressed endogenous TGF-beta responsive genes by microarray analyses. DACH1 bound to endogenous NCoR and Smad4 in cultured cells and DACH1 co-localized with NCoR in nuclear dot-like structures. NCoR enhanced DACH1 repression and the repression of TGF-beta-induced AP-1 or Smad-signaling by DACH1 required the DACH1 DS domain. The DS-domain of DACH was sufficient for NCoR-binding at a Smad4-binding site. Smad4 was required for DACH1 repression of Smad signaling. In Smad4 null HTB-134 cells, DACH1 inhibited the activation of SBE-4 reporter activity induced by Smad2 or Smad3 only in the presence of Smad4. DACH1 participates in the negative regulation of TGF-beta signaling by interacting with NCoR and Smad4.

2007-07-19 | E-GEOD-685 | biostudies-arrayexpress

SMAD4 plays acritical role in CD8 T cell cytotoxic function [RNA-seq]

Project description:Transforming growth factor-beta (TGF-β) restrains cytotoxic immune response to maintain self-tolerance and to promote tumor immune evasion. Yet how SMAD4, a central transcription factor component of TGF-β signaling, regulates CD8+ T cell function remains unclear. Here we have demonstrated SMAD4 played a critical role in promoting CD8+ T cell activation and cytotoxic function. SMAD4-mediated transcriptional regulation of CD8+ T cell activation and cytotoxicity is regulated by T-cell receptor (TCR) signaling pathway rather than TGF-β signaling pathway. We described a new mechanism that in TCR-mediated intracellular signal propagation, SMAD4 markedly translocated into the nucleus, upregulated genes that encoding TCR complex subunits and cytotoxic molecules in CD8+ T cells, reinforced the TCR-activation signals through a positive feedback loop. And in this signaling, SMAD4 is phosphorylated by ERK at Ser367 residue. Our study thus demonstrates an essential role of SMAD4 in promoting CD8+ T cell mediated cytotoxic immune responses.

2022-07-12 | GSE192621 | GEO

SMAD4 plays acritical role in CD8 T cell cytotoxic function [ChIP-seq]

2022-07-12 | GSE192620 | GEO

The TGF-β/SMAD pathway upregulates SRC

Project description:The non-receptor tyrosine kinase SRC is upregulated in various human cancers and plays crucial roles in cancer progression by promoting invasion and metastasis. We show that the transforming growth factor beta (TGF-β/SMAD pathway directly upregulates SRC during the epithelial-mesenchymal transition. In human epithelial MCF10A cells, TGF-β1 treatment markedly upregulated mRNA expression of SRC. Knockout of SMAD4 suppressed upregulation of SRC by TGF-β1. ChIP-sequencing analysis revealed that SRC was transcribed from the SRC1A promoter, which interacted with SMAD2 and SMAD4, in response to TGF-β1. These findings demonstrate that a direct interaction of the activated SMAD complex with the SRC1A promoter directly upregulates SRC and suggest that TGF-β contributes to SRC upregulation in the tumor microenvironment, where TGF-β-mediated tumor progression takes place.

2023-11-20 | GSE122913 | GEO

Gene expression analyses of SMAD4 knockdown in pancreatic cell line

Project description:The transforming growth factor β (TGF-β) signaling protein SMAD4 is lost in 60% of PDAC, and this has been associated with poorer prognosis. We expressed SMAD4 in human PDAC cell lines BxPC3, by selection of stable clones containing an inducible SMAD4 Tet-ON construct. After 24h of SMAD4 expression, TGF-β signaling-dependent G1-arrest was observed in BxPC3 cells with an increase in the G1-phase fraction from 48.9% to 71.5%. Microarray analysis of gene expression at 8h, 24h, and 48h after SMAD4 expression characterized the regulatory impact of SMAD4 expression in a SMAD4-null PDAC cell line and identified novel targets of TGF-β signaling.

2015-08-20 | GSE70940 | GEO

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