STAT5 and STAT3 balance shapes dendritic cell function and tumor immunity
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ABSTRACT:
PROVIDER: PRJNA1224740 | ENA |
REPOSITORIES: ENA
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Project description:Immune checkpoint blockade (ICB) has transformed cancer therapy. Therapeutic efficacy of ICB depends on dendritic cell (DC)-mediated tumor antigen presentation, T-cell priming and activation. However, the relationship between the key transcription factors in DCs and ICB efficacy remains unknown. Here, we discover that ICB reprogramed the interplay between the STAT3 and STAT5 transcriptional pathways in DCs, thereby activating T-cell immunity, and enabling ICB efficacy in cancer patients and tumor bearing mice. Mechanistically, STAT3 competed with STAT5 for JAK interaction, determining the fate of DC function. As STAT3 is often activated in the tumor microenvironment (TME), we designed specific PROTAC degraders of STAT3, SD-36 and SD-2301. Low doses of SD-36 selectively and preferentially degraded STAT3 in DCs and reprogramed the DC transcriptional network toward immunogenicity. Furthermore, SD-36 monotherapy efficiently treated mice bearing large, advanced tumors and ICB resistant tumors without any signs of toxicity. Notably, SD2301 exhibits superior therapeutic efficacy compared to SD-36. Thus, the crosstalk between STAT3 and STAT5 determines DC phenotype in the TME and STAT3-degradation holds promise for cancer immunotherapy.
2025-05-14 | GSE289764 | GEO
Project description:Interleukin 2 (IL-2), a cytokine linked to human autoimmune diseases, limits IL-17 production. We show that deletion of Stat3 in T cells abrogates IL-17 production and attenuates autoimmunity associated with IL-2 deficiency. While STAT3 induces IL-17 and RORγt and inhibits Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. We found that STAT3 and STAT5 bound to multiple common sites across the Il17 genetic locus. The induction of STAT5 binding by IL-2 was associated with a reduction in STAT3 binding at these sites and the inhibition of associated active epigenetic marks. Titrating the relative activation of STAT3 and STAT5 modulated TH17 cell specification. Thus, the balance rather than the absolute magnitude of these signals determines the propensity of cells to make a key inflammatory cytokine. The genome-wide binding of STAT3 and STAT5 under Th17 conditions was investigated by CHIP-seq.
2011-02-09 | E-GEOD-26552 | biostudies-arrayexpress
Project description:Interleukin 2 (IL-2), a cytokine linked to human autoimmune diseases, limits IL-17 production. We show that deletion of Stat3 in T cells abrogates IL-17 production and attenuates autoimmunity associated with IL-2 deficiency. While STAT3 induces IL-17 and ROR?t and inhibits Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and ROR?t. We found that STAT3 and STAT5 bound to multiple common sites across the Il17 genetic locus. The induction of STAT5 binding by IL-2 was associated with a reduction in STAT3 binding at these sites and the inhibition of associated active epigenetic marks. Titrating the relative activation of STAT3 and STAT5 modulated TH17 cell specification. Thus, the balance rather than the absolute magnitude of these signals determines the propensity of cells to make a key inflammatory cytokine. The roles of STAT3 and STAT5 in regulation of gene expression under Th17 differentiation was investigated. Affymetrix Mouse Genome 430 2.0 Arrays were used to evaluate global gene expression.
2011-02-09 | E-GEOD-26551 | biostudies-arrayexpress
Project description:Interleukin 2 (IL-2), a cytokine linked to human autoimmune diseases, limits IL-17 production. We show that deletion of Stat3 in T cells abrogates IL-17 production and attenuates autoimmunity associated with IL-2 deficiency. While STAT3 induces IL-17 and RORγt and inhibits Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. We found that STAT3 and STAT5 bound to multiple common sites across the Il17 genetic locus. The induction of STAT5 binding by IL-2 was associated with a reduction in STAT3 binding at these sites and the inhibition of associated active epigenetic marks. Titrating the relative activation of STAT3 and STAT5 modulated TH17 cell specification. Thus, the balance rather than the absolute magnitude of these signals determines the propensity of cells to make a key inflammatory cytokine.
2011-02-09 | GSE26552 | GEO
Project description:Interleukin 2 (IL-2), a cytokine linked to human autoimmune diseases, limits IL-17 production. We show that deletion of Stat3 in T cells abrogates IL-17 production and attenuates autoimmunity associated with IL-2 deficiency. While STAT3 induces IL-17 and RORγt and inhibits Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. We found that STAT3 and STAT5 bound to multiple common sites across the Il17 genetic locus. The induction of STAT5 binding by IL-2 was associated with a reduction in STAT3 binding at these sites and the inhibition of associated active epigenetic marks. Titrating the relative activation of STAT3 and STAT5 modulated TH17 cell specification. Thus, the balance rather than the absolute magnitude of these signals determines the propensity of cells to make a key inflammatory cytokine.
2011-02-09 | GSE26551 | GEO
Project description:Dendritic cells (DC) play a vital role in the induction of activation or tolerance of immune response. STAT3 is a master transcriptional regulator of immune response in DCs by positively or negatively regulating DC function, but the mechanisms are unknown. STAT3 is post-translationally modified by acetylation or phosphorylation. While much is understood about transcriptional targets of phosphorylated STAT3, the gene targets and the functional impact of acetylated-STAT3 remain unclear. We aimed to answer the gene targets of acetylated-STAT3 and test the hypothesis that acetylation of STAT3 plays a key role in negative regulation of DCs. We performed genome-wide binding analysis of acetyl-STAT3 by ChIP-Seq coupled with gene expression microarrays. Acetylation of STAT3 induced by SAHA increased its capability to bind to target DNA sites in genome. Theses binding sites were mostly proximal but some were also distal up to over 100 kb from transcription start site. Gene expression array showed 1701 genes up-regulated and 1668 genes down-regulated. Proximal binding of acety-STAT3 showed more effective transcription function than distal binding. In top 500 binding peaks, the frequency of canonical motifs bound by acetyl-STAT3 were significantly higher than that for noncanonical motifs (p<0.00001). Functional analysis revealed that acetyl-STAT3 regulates target genes by upregulating genes that are primarily involved in negative regulation of cytokine production and IL-10 signaling, or downregulating genes that are primarily involved in immune effector process and antigen processing/presentation. Upregulation of IL-10Ra by acetyl-STAT3 contributes to the enhanced sensitivity of IL-10 signaling and negative regulation of DC function. Bone marrow derived dendritic cells were treated with SAHA (500 nm) or diluent for 12 hours. ChIP was performed using antibodies against STAT3, H3K4me3 and matched IgG control. DNA binding profiles were generated by deep sequencing using Illumina HiSeq 2000.
2015-11-05 | E-GEOD-74262 | biostudies-arrayexpress
Project description:Cytokines utilize the transcription factor STAT5 to control cell-specific and universal genes. In general, the magnitude of cell-restricted gene activation greatly exceeds that of universal genes, with a mechanistic explanation yet to be supplied. Genome-wide studies have identified putative STAT5-based mammary-specific enhancers and universal STAT5-controlled regulatory elements, an opportunity to investigate mechanisms underlying their differential response to cytokines. We have now interrogated the integrity and function of both categories of regulatory elements using biological and genetic approaches. During lactation, STAT5 occupies mammary-specific and universal cytokine-responsive elements. Following lactation, prolactin levels decline and STAT5-dependent enhancers at mammary-specific genes are decommissioned with 24 hours while universal regulatory complexes remain intact. These differential sensitivities are linked to STAT5 concentrations and the mammary-specific Stat5 autoregulatory enhancer. In its absence, mammary-specific enhancers, but not universal elements, fail to be fully established. Upon termination of lactation, STAT5 binding to a subset of mammary enhancers is substituted by STAT3. No STAT3 binding was observed at the most sensitive STAT5 enhancers, suggesting that upon hormone withdrawal their chromatin becomes inaccessible. This study, for the first time, provides molecular insight into the differential sensitivities of mammary-specific and universal cytokine-sensing enhancers.
2016-09-12 | GSE84115 | GEO
Project description:Transcriptional profiling of mouse osteoclasts comparing control osteoclasts from Stat5 flox mice with osteoclasts from Stat5 cKO mice. Two-condition experiment, Stat5 flox cells vs. Stat5 cKO cells
2013-12-09 | E-GEOD-51283 | biostudies-arrayexpress
Project description:Dendritic cells (DC) play a vital role in the induction of activation or tolerance of immune response. STAT3 is a master transcriptional regulator of immune response in DCs by positively or negatively regulating DC function, but the mechanisms are unknown. STAT3 is post-translationally modified by acetylation or phosphorylation. While much is understood about transcriptional targets of phosphorylated STAT3, the gene targets and the functional impact of acetylated-STAT3 remain unclear. We aimed to answer the gene targets of acetylated-STAT3 and test the hypothesis that acetylation of STAT3 plays a key role in negative regulation of DCs. We performed genome-wide binding analysis of acetyl-STAT3 by ChIP-Seq coupled with gene expression microarrays. Acetylation of STAT3 induced by SAHA increased its capability to bind to target DNA sites in genome. Theses binding sites were mostly proximal but some were also distal up to over 100 kb from transcription start site. Gene expression array showed 1701 genes up-regulated and 1668 genes down-regulated. Proximal binding of acety-STAT3 showed more effective transcription function than distal binding. In top 500 binding peaks, the frequency of canonical motifs bound by acetyl-STAT3 were significantly higher than that for noncanonical motifs (p<0.00001). Functional analysis revealed that acetyl-STAT3 regulates target genes by upregulating genes that are primarily involved in negative regulation of cytokine production and IL-10 signaling, or downregulating genes that are primarily involved in immune effector process and antigen processing/presentation. Upregulation of IL-10Ra by acetyl-STAT3 contributes to the enhanced sensitivity of IL-10 signaling and negative regulation of DC function.
2015-11-05 | GSE74262 | GEO
Project description:Type I conventional dendritic cells (cDC1s) are an essential antigen-presenting population, required for generating adaptive immunity against intracellular pathogens and tumors. While the transcriptional control of cDC1 development is well understood, the mechanisms by which extracellular stimuli affect cDC1 function remain unclear. Recently, we demonstrated that the cytokine IL-10 inhibits cDC1 maturation induced upon polyinosinic-polycytidylic acid (poly I:C) exposure via a STAT3-dependent mechanism. Furthermore, utilizing a tumor vaccine strategy, we found STAT3 restrains cDC1-mediated anti-tumor immunity. To understand the pathways by which IL-10 and STAT3 regulate cDC1s, we evaluated transcriptional responses by RNA-sequencing. Bioinformatic analyses indicated that many inflammatory pathways were enriched in cDC1s following poly I:C treatment, while interferon (IFN) signaling was uniquely inhibited by STAT3 upon concomitant exposure to IL-10. We found that poly I:C stimulated production of IFN-b and IFN-g from cDC1s. Concurrent exposure to IL-10 suppressed IFN-b and IFN-g secretion as well as accrual of phosphorylated STAT1 and expression of the IFN-response gene Cxcl10 in cDC1s. By contrast, Stat3-deficient cDC1s were refractory to IL-10, indicating STAT3 controls poly I:C-mediated IFN production and IFN transcriptional responses in cDC1s. Moreover, we found that maturation of cDC1s in response to poly I:C is dependent on the type I IFN receptor. Taken together, our data indicate STAT3 is essential for restraining autocrine type I IFN signaling in cDC1s elicited by poly I:C stimulation.
2022-07-26 | GSE188995 | GEO