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Rheumatology (Oxford, England) Feb 2024Janus kinases (JAKs) are a family of cytosolic tyrosine kinases that regulate cytokine signal transduction, including cytokines involved in a range of inflammatory... (Review)
Review
Janus kinases (JAKs) are a family of cytosolic tyrosine kinases that regulate cytokine signal transduction, including cytokines involved in a range of inflammatory diseases, such as RA, psoriasis, atopic dermatitis and IBD. Several small-molecule JAK inhibitors (JAKis) are now approved for the treatment of various immune-mediated inflammatory diseases. There are, however, key differences between these agents that could potentially translate into unique clinical profiles. Each JAKi has a unique chemical structure, resulting in a distinctive mode of binding within the catalytic cleft of the target JAK, and giving rise to distinct pharmacological characteristics. In addition, the available agents have differing selectivity for JAK isoforms, as well as off-target effects against non-JAKs. Other differences include effects on haematological parameters, DNA damage repair, reproductive toxicity and metabolism/elimination. Here we review the pharmacological profiles of the JAKis abrocitinib, baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib.
Topics: Humans; Janus Kinase Inhibitors; Antirheumatic Agents; Arthritis, Rheumatoid; Janus Kinases; Psoriasis
PubMed: 37624925
DOI: 10.1093/rheumatology/kead448 -
Cell Reports Feb 2021In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this...
In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this senescence-associated secretory phenotype (SASP) leads to cancer progression and chemoresistance. However, the role of senescent CAFs in metastatic lesions and the molecular mechanism of inflammation-related SASP induction are not well understood. We show that pro-inflammatory cytokine-driven EZH2 downregulation maintains the SASP by demethylating H3K27me3 marks in CAFs and enhances peritoneal tumor formation of gastric cancer (GC) through JAK/STAT3 signaling in a mouse model. A JAK/STAT3 inhibitor blocks the increase in GC cell viability induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry revealed that fibroblasts exist in the ascites of GC patients with peritoneal dissemination, and the fibroblast population shows p16 expression and SASP factors at high levels. These findings provide insights into the inflammation-related SASP maintenance by histone modification and the role of senescent CAFs in GC peritoneal dissemination.
Topics: Aged; Animals; Antineoplastic Agents; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cytokines; Enhancer of Zeste Homolog 2 Protein; Female; Gene Expression Regulation, Neoplastic; Humans; Inflammation Mediators; Janus Kinase Inhibitors; Janus Kinases; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Peritoneal Neoplasms; Pyridines; STAT3 Transcription Factor; Senescence-Associated Secretory Phenotype; Signal Transduction; Stomach Neoplasms; Tumor Microenvironment; Tyrphostins; Xenograft Model Antitumor Assays; Mice
PubMed: 33626356
DOI: 10.1016/j.celrep.2021.108779 -
Molecular Therapy : the Journal of the... Mar 2021Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III...
Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III interferon (IFN), which enhances the immunogenicity of RNA vaccines but can also lead to inhibition of translation. In this study, we screened a library of saRNA constructs with cis-encoded innate inhibiting proteins (IIPs) and determined the effect on protein expression and immunogenicity. We observed that the PIV-5 V and Middle East respiratory syndrome coronavirus (MERS-CoV) ORF4a proteins enhance protein expression 100- to 500-fold in vitro in IFN-competent HeLa and MRC5 cells. We found that the MERS-CoV ORF4a protein partially abates dose nonlinearity in vivo, and that ruxolitinib, a potent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor, but not the IIPs, enhances protein expression of saRNA in vivo. Both the PIV-5 V and MERS-CoV ORF4a proteins were found to enhance the percentage of resident cells in human skin explants expressing saRNA and completely rescued dose nonlinearity of saRNA. Finally, we observed that the MERS-CoV ORF4a increased the rabies virus (RABV)-specific immunoglobulin G (IgG) titer and neutralization half-maximal inhibitory concentration (IC) by ∼10-fold in rabbits, but not in mice or rats. These experiments provide a proof of concept that IIPs can be directly encoded into saRNA vectors and effectively abate the nonlinear dose dependency and enhance immunogenicity.
Topics: Animals; Cell Line; Encephalitis Virus, Venezuelan Equine; Fibroblasts; Gene Expression Regulation; HeLa Cells; Host-Pathogen Interactions; Humans; Immunity, Innate; Immunogenicity, Vaccine; Immunoglobulin G; Interferon Regulatory Factor-3; Janus Kinases; Mice; Middle East Respiratory Syndrome Coronavirus; NF-kappa B; Nitriles; Parainfluenza Virus 5; Protein Biosynthesis; Pyrazoles; Pyrimidines; Rabbits; Rabies virus; Rats; STAT Transcription Factors; Signal Transduction; Vaccines, Synthetic; Viral Envelope Proteins; mRNA Vaccines
PubMed: 33352107
DOI: 10.1016/j.ymthe.2020.11.011 -
Biomedicine & Pharmacotherapy =... Nov 2022IFN-γ, a soluble cytokine being produced by T lymphocytes, macrophages, mucosal epithelial cells, or natural killer cells, is able to bind to the IFN-γ receptor... (Review)
Review
Role of interferon-gamma (IFN-γ) and IFN-γ receptor 1/2 (IFNγR1/2) in regulation of immunity, infection, and cancer development: IFN-γ-dependent or independent pathway.
IFN-γ, a soluble cytokine being produced by T lymphocytes, macrophages, mucosal epithelial cells, or natural killer cells, is able to bind to the IFN-γ receptor (IFNγR) and in turn activate the Janus kinase (JAK)-signal transducer and transcription protein (STAT) pathway and induce expression of IFN-γ-stimulated genes. IFN-γ is critical for innate and adaptive immunity and aberrant IFN-γ expression and functions have been associated with different human diseases. However, the IFN-γ/IFNγR signaling could be a double-edged sword in cancer development because the tissue microenvironments could determine its anti- or pro-tumorigenic activities. The IFNγR protein consists of two IFNγR1 and IFNγR2 chains, subunits of which play different roles under certain conditions. This review assessed IFNγR polymorphisms, expression and functions in development and progression of various human diseases in an IFN-γ-dependent or independent manner. This review also discussed tumor microenvironment, microbial infection, and vital molecules in the IFN-γ upstream signaling that might regulate IFNγR expression, drug resistance, and druggable strategy, to provide evidence for further application of IFNγR.
Topics: Humans; Interferon-gamma; Receptors, Interferon; Janus Kinases; Neoplasms; STAT1 Transcription Factor; Tumor Microenvironment; Interferon gamma Receptor
PubMed: 36095965
DOI: 10.1016/j.biopha.2022.113683 -
Cells Jan 2020The JAK/STAT3 signaling pathway plays an essential role in various types of cancers. Activation of this pathway leads to increased tumorigenic and metastatic ability,... (Review)
Review
The JAK/STAT3 signaling pathway plays an essential role in various types of cancers. Activation of this pathway leads to increased tumorigenic and metastatic ability, the transition of cancer stem cells (CSCs), and chemoresistance in cancer via enhancing the epithelial-mesenchymal transition (EMT). EMT acts as a critical regulator in the progression of cancer and is involved in regulating invasion, spread, and survival. Furthermore, accumulating evidence indicates the failure of conventional therapies due to the acquisition of CSC properties. In this review, we summarize the effects of JAK/STAT3 activation on EMT and the generation of CSCs. Moreover, we discuss cutting-edge data on the link between EMT and CSCs in the tumor microenvironment that involves a previously unknown function of miRNAs, and also discuss new regulators of the JAK/STAT3 signaling pathway.
Topics: Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Humans; Janus Kinases; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; STAT3 Transcription Factor; Signal Transduction
PubMed: 31952344
DOI: 10.3390/cells9010217 -
Nature Communications Feb 2022Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the... (Observational Study)
Observational Study
Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1 myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies.
Topics: Adult; Aged; Brain Neoplasms; Cell Communication; Cell Line, Tumor; Female; Glioblastoma; Healthy Volunteers; Heme Oxygenase-1; Humans; Immunotherapy; Interleukin-10; Janus Kinase Inhibitors; Janus Kinases; Male; Middle Aged; Myeloid Cells; Neocortex; Primary Cell Culture; RNA-Seq; STAT Transcription Factors; Signal Transduction; Single-Cell Analysis; T-Lymphocytes; Tissue Culture Techniques; Tumor Escape; Tumor Microenvironment
PubMed: 35177622
DOI: 10.1038/s41467-022-28523-1 -
Blood Dec 2021Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better...
Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (P = .05). Our findings indicate that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. This trial was registered at www.clincialtrials.gov as #NCT02974647.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Janus Kinases; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Nitriles; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; STAT Transcription Factors; Treatment Outcome; Young Adult
PubMed: 34653242
DOI: 10.1182/blood.2021013379 -
Nature Cancer Sep 2022Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic...
Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated. We reveal that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer. Importantly, ectopic JAK-STAT activation is specifically required for the resistance of stem-like subclones expressing multilineage transcriptional programs but not subclones exclusively expressing the neuroendocrine-like lineage program. Both genetic and pharmaceutical inhibition of JAK-STAT signaling resensitizes resistant tumors to AR-targeted therapy. Together, these results suggest that JAK-STAT are compelling therapeutic targets for overcoming lineage plasticity-driven AR-targeted therapy resistance.
Topics: Humans; Janus Kinases; Male; Pharmaceutical Preparations; Prostatic Neoplasms; Receptors, Androgen; STAT Transcription Factors
PubMed: 36065066
DOI: 10.1038/s43018-022-00431-9 -
The Journal of Allergy and Clinical... Oct 2021Asthma is an inflammatory disease of the airways characterized by intermittent episodes of wheezing, chest tightness, and cough. Many of the inflammatory pathways... (Review)
Review
Asthma is an inflammatory disease of the airways characterized by intermittent episodes of wheezing, chest tightness, and cough. Many of the inflammatory pathways implicated in asthma involve cytokines and growth factors that activate Janus kinases (JAKs). The discovery of the JAK/signal transducer and activator of transcription (STAT) signaling pathway was a major breakthrough that revolutionized our understanding of cell growth and differentiation. JAK inhibitors are under active investigation for immune and inflammatory diseases, and they have demonstrated clinical efficacy in diseases such as rheumatoid arthritis and atopic dermatitis. Substantial preclinical data support the idea that inhibiting JAKs will ameliorate airway inflammation and hyperreactivity in asthma. Here, we review the rationale for use of JAK inhibitors in different asthma endotypes as well as the preclinical and early clinical evidence supporting such use. We review preclinical data from the use of systemic and inhaled JAK inhibitors in animal models of asthma and safety data based on the use of JAK inhibitors in other diseases. We conclude that JAK inhibitors have the potential to usher in a new era of anti-inflammatory treatment for asthma.
Topics: Animals; Asthma; Drug Administration Routes; Humans; Janus Kinase Inhibitors; Janus Kinases; STAT Transcription Factors
PubMed: 34625142
DOI: 10.1016/j.jaci.2021.08.013 -
Frontiers in Immunology 2021Cellular therapies such as allogeneic hematopoietic stem cell transplantation (HSCT) and immune-effector cell therapy (IECT) continue to have a critical role in the... (Review)
Review
Cellular therapies such as allogeneic hematopoietic stem cell transplantation (HSCT) and immune-effector cell therapy (IECT) continue to have a critical role in the treatment of patients with high risk malignancies and hematologic conditions. These therapies are also associated with inflammatory conditions such as graft--host disease (GVHD) and cytokine release syndrome (CRS) which contribute significantly to the morbidity and mortality associated with these therapies. Recent advances in our understanding of the immunological mechanisms that underly GVHD and CRS highlight an important role for Janus kinases (JAK). JAK pathways are important for the signaling of several cytokines and are involved in the activation and proliferation of several immune cell subsets. In this review, we provide an overview of the preclinical and clinical evidence supporting the use of JAK inhibitors for acute and chronic GVHD and CRS.
Topics: Animals; Cytokine Release Syndrome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Janus Kinase Inhibitors; Janus Kinases; Signal Transduction
PubMed: 34531878
DOI: 10.3389/fimmu.2021.740847