The IFN-I-DUSP2-NFAT axis Limits Tumor Remodeling and Immunotherapy Response in Lung Cancer
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PROVIDER: PRJNA1291128 | ENA |
REPOSITORIES: ENA
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Project description:Type I interferons (IFN-I) exert context-dependent effects in tumor microenvironment (TME), but their role in shaping immunotherapy response remains unclear. Here, we performed single-cell RNA sequencing of lung squamous cell carcinoma (LUSC) samples collected before and after immune checkpoint blockade (ICB), stratified by treatment outcome. In responders, ICB induced B cell and T follicular helper (Tfh) cell expansion, promoting the formation of tertiary lymphoid structure (TLS)-like niche. By contrast, non-responders exhibited sustained IFN-I signaling and accumulation of CD36⁺ SPP1⁺ tumor-associated macrophages (TAMs), which secreted IFN-I and disrupted lymphoid aggregation. At baseline, aberrant NFAT signaling in T cells marked a dysfunctional state. Mechanistically, IFN-I upregulated the phosphatase DUSP2 in pre-exhausted T cells, which dephosphorylated NFAT and promoted its nuclear localization. Nuclear NFAT transactivated genes encoding inhibitory receptors to reinforce T cell exhaustion. Deletion of Dusp2 restored CD8+ T cell function and Tfh-B cell interaction, improving response to PD-1 blockade. These findings identify a pathogenic IFN-I-DUSP2-NFAT axis that constrains immunotherapy efficacy in LUSC.
2025-07-19 | GSE302517 | GEO
Project description:Zika virus (ZIKV) is unique among mosquito-borne flaviviruses in its ability to be sexually transmitted. The testes have been implicated as sites of long-term ZIKV replication, and our previous studies have identified Sertoli cells (SC), the nurse cells of the seminiferous epithelium that govern spermatogenesis, as major targets of ZIKV infection. To improve our understanding of the host-ZIKV interaction within human testicular cells, we analyzed ZIKV-induced proteome changes in SC and mixed seminiferous tubule cells (STC) using high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that ZIKV infection in SC and STC induced distinct IFN-stimulated proteins and impacted pathways and functional networks associated with innate antiviral defense. IFN signaling was the most significantly enriched pathway and MX1 was the most abundant IFN-stimulated protein in both SC and STC. Increased levels of MX1 at later time points of infection coincided with diminished propagation of ZIKV in SC, whereas silencing of MX1 and IFIT1 enhanced peak ZIKV titers in SC. Furthermore, although downstream IFN-I signaling was found to be functional and restricted ZIKV replication in SC, in comparison to A549 cells, SC exhibited dampened expression of IFN-I/III-stimulated genes despite higher levels of virus progeny and IFN-I/III transcripts. Together, this study highlights the IFN-I/III response as a driver of the antiviral state that limits ZIKV infection in SC and suggests that delayed and reduced robustness of innate antiviral defense in SC may contribute to ZIKV persistence in the testes.
2021-09-10 | PXD025133 | Pride
Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A. bone marrow cells from C57B/6 mice were stimulated in Flt3-L suplemented media in presence or absence of calcineurin/NFAT inhibitor Cyclosporin A, samples in 3 biological replicates
2011-09-30 | E-GEOD-29094 | biostudies-arrayexpress
Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A.
2011-10-01 | GSE29094 | GEO
Project description:The nephrotoxic ifosfamide-metabolite chloroacetaldehyde (CAA) induces changes in intracellular Ca2+-concentration of human RPTEC. This effect is due to a PKA-dependent inhibition of Na+/Ca2+ exchange (Benesic, A., Schwerdt, G. at. al. (2005) Kidney Int 68, 2029-2041). Thus, possible effects of CAA-exposure on cAMP and Ca2+ regulated genes as well the Ca2+/NFAT pathway were investigated by cDNA-microarray analysis. Both microarrays (cAMP/Ca2+ and Ca2+(NFAT) were performed twice. After 24 h CAA exposure a marked downregulation of c-fos and junB was observed in all arrays performed. In the cAMP/Ca2+-arrays downregulation of FOS, ADRB1, INHBA, CDK5, IL2, PLN, SRF, GCG, SGK, JUNB, BDNF, S100A6, CCNA1, MIF, HK2, SST and EGR2 by CAA was observed in two independent experiments. From the AP-1 family expression of junD and fosB were not altered. Overexpression by CAA of CREB and DDIT3 were only observed in one of two experiments. JUND, FOSB, FOSL1, CREM and CREBBP expression was not influenced in reproducible manner, as well as all members of the NFAT-family. In the Ca2+/NFAT-Arrays, PPP3CB, VAV3, NFATC1, IL8, IL6, FASLG, IL3, IFNB1, FOS, BCL2, EGR3, CD3G, HRAS, EP300, IL4, CALM3, RELA, EGR2, NPPB, IFNG, NFATC4, KPNA5, CAMK2BNFKB2 , VEGF, IL8RA, IL2,GATA4, MEF2A, PTPRC, ICOS, NFKBIE, CDKN1A, CSNK2B, ACTB, MEF2B and JUNB mRNA´s were repeatedly reduced by CAA exposure. The only gene with upregulation in both experiments was found to be IFN-alpha. Thus CAA exposure for 24 h leads to a downregulation of of the AP-1 members JUNB and FOS, whereas there is small positive effect on CREB mRNA. CAA reproducibly lowers the expression of IL-2, 3, 4, 6 and 8, whereas the levels of TNFalpha and TGFbeta1 and 3 mRNA were not altered. IFN-alpha mRNA levels were reproducibly increased (>2-fold). In conclusion, CAA seems to interact with Ca2+ and cAMP signalling pathways, with a strong impact on AP-1 proteins and inflammatory signalling. Keywords: stress response to toxic agent
2006-06-30 | GSE4956 | GEO
Project description:Tumor endothelial up-regulation of IDO1 limits the response to CD40-stimulating immunotherapy
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Project description:Cytomegalovirus (CMV) induces a uniquely robust and persistent T cell response, where the size of the antigen-specific population does not contract, but rather inflates during viral latency. It has been proposed that intermittent engagements of T cell receptors (TCRs) by viral antigens upon subclinical episodes of virus reactivation feed the inflation of CMV-specific memory cells, but evidence of TCR engagement has remained lacking. Nuclear factor of activated T cells (NFAT) is a family of transcription factors, where NFATc1, NFATc2 and NFATc3 are expressed in mature T lymphocytes, of which NFATc1 and NFATc2 are the dominating family members. In an in vivo model of mouse CMV (MCMV) infection of mice with genetic ablation of NFAT signaling, we show a selective impact of this defect in TCR signaling on the long-term inflation of MCMV-specific CD8 T cell responses, while the initial responses to acute infection remain largely maintained. NFATc1 ablation had an immediate effect, while ablation of both NFATs had the most profound influence. In presence of other lymphocytes, NFAT deficiency in T cells had no effect on virus replication or latency, but in adoptive immunotherapy of RAG2-deficient recipient mice, the lack of both NFAT molecules in solely transplanted CD8+ T cells uncovered their decreased antiviral efficacy. We characterized CD8 responses in absence of either or both NFAT molecules by transcriptome analyses and demonstrate that T cell-intrinsic NFAT is not necessary for CD8 T cell priming, but rather for their maturation towards effector memory and in particular the effector cells, which dominate the pool of inflationary cells.
2024-01-25 | GSE228527 | GEO
Project description:Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator of store-operated Ca2+ entry (SOCE) triggering activation of transcription factors. Here, we characterize Stim1A, a splice variant with an additional 31 amino acid domain inserted in frame within its cytosolic domain. Prominent expression of exon A is found in astrocytes, heart, kidney and testes. Full length Stim1A functions as a dominant-negative regulator of SOCE and ICRAC, facilitating sequence specific fast calcium dependent inactivation and destabilizing gating or Orai1. Downregulation or absence of native Stim1A results in increased SOCE. Despite reducing SOCE, Stim1A leads to increased NFAT translocation. Differential proteomics revealed interference of Stim1A with the cAMP-SOCE crosstalk by altered modulation of phosphodiesterase (PDE8B), resulting in reduced cAMP degradation and increased PIP5K activity, facilitating an increased NFAT activation. Our study uncovers a hitherto unknown mechanism regulating NFAT activation and indicates that cell type specific splicing of Stim1 is a potent means to regulate the NFAT signalosome and cAMP-SOCE crosstalk.
2021-11-11 | PXD028974 | Pride
Project description:Diffuse large B-cell lymphoma (DLBCL) represents the most common form of lymphoma. We could show that in DLBCL cell lines the transcription factor NFAT is constitutively activated and drives the survival of a DLBCL subset. Aim of the analysis was to identify NFAT target genes in a NFAT-dependent (HBL-1) or -independent (HT) DLBCL cell line. To block NFAT activity, the DLBCL cells were treated with the calcineurin inhibitor cyclosporin A (CsA) up to 48 h. With this approach, we identified several survival-related NFAT target genes in HBL-1 cells that might explain the toxic effects of calcineurin inhibitors.
2019-11-23 | GSE140882 | GEO
Project description:Tumors entertain a highly immunosuppressive network by merging features of regulatory cytokines and cell populations to evade immune control. Myeloid-derived suppressor cells (MDSC) comprise populations of immature myeloid cells in tumor-bearing hosts with a highly immunosuppressive capacity. We could previously identify RIG-I-like helicases (RLH) as targets for the immunotherapy of pancreatic cancer inducing immunogenic tumor cell death and type I interferons (IFN), as key mediators linking innate with adaptive immunity. Here, we show that autochthonous type I IFN signaling is critical for MDSC to gain suppressive function. In contrast, RNA sequencing of MDSC from RLH-ligand-treated mice showed an IFN-driven gene signature and a switch from a M2/G2- towards a M1/G1-polarized phenotype. Functional assays confirmed the loss of the T cell suppressive capacity. Our study identifies a dual role of type I IFN signaling in MDSC´s suppressive function, and RLH-mediated tumor control.
2019-11-19 | GSE126879 | GEO