Interleukin-1 Receptor Research Articles

STAT3 and the STAT3‑regulated inhibitor of apoptosis protein survivin as potential therapeutic targets in colorectal cancer (Review).

Colorectal cancer (CRC) is one of the leading types of cancer worldwide. CRC development has been associated with the constitutive activation of signal transducer and activator of transcription 3 (STAT3). STAT3 is a master regulator of inflammation during cancer-associated colitis, and becomes upregulated in CRC. In CRC, STAT3 is activated by IL-6, among other pro-inflammatory cytokines, inducing the expression of target genes that stimulate proliferation, angiogenesis and the inhibition of apoptosis. One of the main STAT3-regulated inhibitors of apoptosis is survivin, which is a bifunctional protein that regulates apoptosis and participates in cell mitosis. Survivin expression is normally limited to foetal tissue; however, survivin is also upregulated in tumours. In silico and experimental analyses have shown that the STAT3 interactome is relevant during CRC progression, and the constitutive STAT3-survivin axis participates in development of the tumour microenvironment and response to therapy. The presence of a STAT3-survivin axis has been documented in CRC cohorts, and the expression of these molecules is associated with poor prognosis and a higher mortality rate in patients with CRC. Thus, STAT3, survivin, and the upstream activators IL-6 and IL-6 receptor, are considered therapeutic targets for CRC. Efforts to develop drugs targeting the STAT3-survivin axis include the evaluation of phytochemical compounds, small molecules and monoclonal antibodies. In the present review, the expression, function and participation of the STAT3-survivin axis in the progression of CRC were investigated. In addition, an update on the pre-clinical and clinical trials evaluating potential treatments targeting the STAT3-survivin axis is presented.

Redundancy in Innate Immune Pathways That Promote CD8+ T-Cell Responses in AAV1 Muscle Gene Transfer.

While adeno-associated viral (AAV) vectors are successfully used in a variety of in vivo gene therapy applications, they continue to be hampered by the immune system. Here, we sought to identify innate and cytokine signaling pathways that promote CD8+ T-cell responses against the transgene product upon AAV1 vector administration to murine skeletal muscle. Eliminating just one of several pathways (including DNA sensing via TLR9, IL-1 receptor signaling, and possibly endosomal sensing of double-stranded RNA) substantially reduced the CD8+ T-cell response at lower vector doses but was surprisingly ineffective at higher doses. Using genetic, antibody-mediated, and vector engineering approaches, we show that blockade of at least two innate pathways is required to achieve an effect at higher vector doses. Concurrent blockade of IL-1R1 > MyD88 and TLR9 > MyD88 > type I IFN > IFNaR pathways was often but not always synergistic and had limited utility in preventing antibody formation against the transgene product. Further, even low-frequency CD8+ T-cell responses could eliminate transgene expression, even in MyD88- or IL-1R1-deficient animals that received a low vector dose. However, we provide evidence that CpG depletion of vector genomes and including TLR9 inhibitory sequences can synergize. When this construct was combined with the use of a muscle-specific promoter, transgene expression in muscle was sustained with minimal local or systemic CD8+ T-cell response. Thus, innate immune avoidance/blockade strategies by themselves, albeit helpful, may not be sufficient to prevent destructive cellular responses in muscle gene transfer because of the redundancy of immune-activating pathways.

Mechanisms of Cinnamomi Cortex against Diabetes Mellitus Explored by Network Pharmacology combined with Molecular Docking and Experimental Validation.

Cinnamomi cortex (CC), a traditional Chinese herbal medicine, exhibits antidiabetic properties, yet the underlying mechanisms are not fully understood. Our study combined network pharmacology, molecular docking, and experimental validation to elucidate the antidiabetic mechanisms of CC. Active components of CC and their potential antidiabetic targets were identified through TCMSP, DisGeNET, and GeneCards. The PPI networks were constructed with STRING and analyzed with Cytoscape, while GO and KEGG analyses utilized the DAVID database. Molecular docking with core targets was performed using Autodock Vina. The efficacy of CC in diabetes mellitus was evaluated through H&E staining, qPCR, and Western blot in the T2DM mouse. Eleven active components and sixty-six potential antidiabetic targets of CC were identified. The enrichment analysis revealed 288 GO terms and 37 pathways. The molecular docking showed high affinity for PPAR-γ and IL-6 receptors. In vivo studies further confirmed CC's ability to modulate PPAR-γ and IL-6, contributing to its antidiabetic effects. CC manages diabetes by regulating the PPAR-γ pathway and suppressing associated inflammation, providing a multi-pathway therapeutic approach.

Sinonasal Outcomes Obtained after 2 Years of Treatment with Benralizumab in Patients with Severe Eosinophilic Asthma and CRSwNP: A "Real-Life" Observational Study.

Benralizumab is a monoclonal antibody that targets the interleukin-5 receptor (IL-5Rα), leading to the rapid depletion of blood eosinophils. RCTs have demonstrated efficacy in patients with severe eosinophilic asthma (SEA). The aim of this study was to assess the efficacy of benralizumab on sinonasal outcomes in a real-life setting in patients with SEA and concomitant chronic rhinosinusitis with nasal polyps (CRSwNP). We included 25 patients (mean age: 57.47 years, range: 35-77, F/M = 12:13) who were prescribed 30 mg benralizumab every month for the first three administrations and then every 2 months. The primary endpoint was to evaluate changes in the SinoNasal Outcome Test-22 (SNOT-22) and nasal polyp score (NPS) over a 24-month treatment period. Secondary endpoints included measuring the effects on nasal obstruction and impaired sense of smell. The mean NPS score decreased significantly from 5.11 ± 1.84 at baseline to 2.37 ± 1.96 at 24 months. The mean SNOT-22 decreased from 57 ± 15.30 at baseline to 26 ± 16.73 at 24 months. The SSIT-16 mean score improved with an increase in olfactory performance from 5.23 ± 2.58 at baseline to 7 ± 3.65 at 24 months. Moreover, 8/25 patients (32%) required rescue treatment with systemic steroids and 2 patients required endoscopic sinus surgery. While the improvement may not seem optimal at 12 months, a progressive enhancement was noted during the second year of treatment. Despite our data showing an improvement in quality of life and a reduction in the size of nasal polyps, no significant improvement in olfactory sensitivity was observed. In addition, in several patients, rescue treatments were required to maintain control of nasal and sinus symptoms. A careful risk-benefit assessment is therefore needed when deciding to continue treatment, weighing the potential for further improvement against the risks of complications. Such decisions should always be made in the context of a multidisciplinary team.

Effect of IL-7 and IL-7R blockade on cytokine production by peripheral blood t cells from patients with psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory joint disease, often associated with psoriasis. Interactions between immune cells, mainly T lymphocytes, and cells of the osteoarticular system are central in the pathogenesis of PsA. Th1, Th17 cytokines associated with the development of PsA contribute to an increase in the production of cytokines, chemokines, matrix metalloproteinases, adhesion molecules by immune cells, chondrocytes, fibroblasts, and induction of osteoclasts. That leads to the destruction of cartilage and bone tissue. Among the cytokines potentially involved in the pathogenesis of PsA, IL-7 is of particular interest. IL-7 is a T cell survival factor. However, it can promote the production of IFNγ and TNFα by T cells. IL-7 may indirectly promote osteoclast maturation and cartilage degradation. The aim was to investigate the effect of IL-7 and blockade of the α-chain of the IL-7 receptor (IL-7R) in vitro on the production of IL-5, IL-13, IL-2, IL-6, IL-9 IL-10, IFNγ, TNFα, IL-17A, IL-17F, IL-4, and IL-22 by T cells in norm and PsA.The study included 14 patients with PsA in the acute stage of the disease and 8 healthy individuals. To determine cytokines concentration, multiplex analysis was performed using flow cytometry.It was shown that IL-7 enhances the production of Th1, Th2, Th17, Th22, and Th9 cytokines in both patients with PsA and healthy individuals. The exception was IL-2 for both groups. Under the blockade of IL-7R with monoclonal antibodies, the level of IL-6 increases and production of IFNγ, TNFα, IL-17F, IL-10, IL-5, and IL-9 by donors’ cells and production of IFNγ, TNFα, IL-22, IL-2, IL-4, IL-5, IL-13, and IL-9 by cells from patients with PsA decreases relative to production of cells stimulated with IL-7. In donors, the blockade contributed to a change in the balance of Th1/Th2 cytokines: level of IL-4, IL-13 did not change on the background of a decrease in production of IFNγ, TNFα. In patients with PsA, under blockade of IL-7R the production of IL-10 remained at an increased level and concentration of IFNγ, TNFα and IL-2, which are actively involved in the tissue damage mechanisms, decreased. The obtained data indicate the prospect of using the IL-7R as a target for the treatment of psoriatic diseases.

Abstract C067: Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review

Abstract Introduction: The introduction of immunotherapy, particularly programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, has transformed the treatment paradigm for non-small cell lung adenocarcinoma (NSCLC), significantly improving patient survival rates. However, alongside their immune-activating effects, these agents can also lead to immune-related adverse events (irAEs), affecting various organ systems. Among these, immune thrombocytopenia (ITP) is a rare but potentially life-threatening complication characterized by the destruction of platelets by autoantibodies, resulting in decreased platelet counts and an increased risk of bleeding. While ITP has been identified as a complication of immunotherapy, particularly PD-1 or PD-L1 inhibitors, its incidence, clinical presentation, and management remain poorly understood. Case Presentation: The 73-year-old female with stage IIIA poorly differentiated NSCLC who received chemotherapy with Taxol/Carboplatin and concurrent radiation therapy followed by a right upper lobectomy, initiated on immunotherapy with durvalumab, a PD-L1 inhibitor, developed severe thrombocytopenia (grade 4) after receiving two cycles of durvalumab. Despite steroid treatment, her condition persisted, indicating immune-related adverse events (irAEs). After confirming the diagnosis through further investigation, including molecular analysis, the patient was treated with intravenous immunoglobulin (IVIG), which significantly increased her platelet counts. Durvalumab was discontinued, and fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, was initiated to manage the irAEs effectively. Discussion: ITP is recognized as an immune-related adverse event (irAE) associated with PD-1 or PD-L1 inhibitors, although it remains rare and poorly understood. Several case reports have highlighted the occurrence of ITP induced by these inhibitors, demonstrating varied clinical presentations and responses to treatment. Mechanisms underlying ITP induction by PD-1/PD-L1 inhibitors are not fully elucidated but may involve immune dysregulation, including CD4+ and CD8+ T cell activation, production of antiplatelet antibodies, and increased expression of PD-L1 on platelets. Management strategies for ITP induced by PD-1/PD-L1 inhibitors include steroids, intravenous immunoglobulin (IVIG) therapy, recombinant human thrombopoietin (TPO), interleukin-6 (IL-6) receptor antagonists, and immunosuppressive agents. However, the effectiveness of these treatments varies among patients, highlighting the need for individualized approaches and further research to optimize management strategies. Conclusion: The prompt recognition and management of ITP induced by PD-1/PD-L1 inhibitors are essential for ensuring favorable patient outcomes. Further research is needed to understand the underlying mechanisms and develop effective prevention and management strategies for this rare but serious immune-related adverse event. Citation Format: Aliya M Khan, Richa Dawar. Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C067.

Relationship of proteins and subclinical cardiovascular traits in the population-based LIFE-Adult study

Background and aimsUnderstanding molecular processes of the early phase of atherosclerotic cardiovascular disease conditions is of utmost importance for early prediction and intervention measures. MethodsWe measured 92 cardiovascular-disease-related proteins (Olink, Cardiovascular III) in 2024 elderly participants of the population-based LIFE-Adult study. We analysed the impact of 27 covariables on these proteins including blood counts, cardiovascular risk factors and life-style-related parameters. We also analysed protein associations with 13 subclinical cardiovascular traits comprising carotid intima media thickness, plaque burden, three modes of Vicorder-based pulse-wave velocities, ankle-brachial index and ECLIA-based N-terminal prohormone of brain natriuretic peptide (NT-proBNP). ResultsEstimated glomerular filtration rate, triglycerides and sex where the most relevant covariables explaining more than 1 % variance of 49, 22 and 20 proteins, respectively. A total of 43 proteins were significantly associated with at least one of the analysed subclinical cardiovascular traits. NT-pro-BNP, brachial-ankle pulse-wave velocity (baPWV) and parameters of carotid plaque burden accounted for the largest number of associations. Association overlaps were relatively sparse. Only growth/differentiation factor 15, low density lipoprotein receptor and interleukin-1 receptor type 2 are associated with these three different cardiovascular traits. We confirmed several literature findings and found yet unreported associations for carotid plaque presence (von-Willebrand factor, galectin 4), carotid intima-media thickness (carboxypeptidase A1 andB1), baPWV (cathepsin D) and NT-proBNP (cathepsin Z, low density lipoprotein receptor, neurogenic locus homolog protein 3, trem-like transcript 2). Sex-interaction effects were observed, e.g. for spondin-1 and growth/differentiation factor 15 likely regulated by androgen response elements. ConclusionsWe extend the catalogue of proteome biomarkers possibly involved in early stages of cardiovascular disease pathologies providing targets for early risk prediction or intervention strategies.

Immunogenicity of Pneumococcal Polysaccharide Vaccine in patients with rheumatoid arthritis

The presented review searched for articles in the databases PubMed, Web of Science, Scopus, Google Scholar, eLibrary (2002-2022) and assessed the immunogenicity of the 23-valent polysaccharide pneumococcal vaccine (PPV23) in adult patients with rheumatoid arthritis (RA), receiving various antirheumatic drugs. The results of this review indicated sufficient immunogenicity of PPV23 in RA patients receiving monotherapy with various biological drugs (bDMARDs) (TNFα inhibitors, IL6 receptor inhibitors, T-lymphocyte costimulation blockers), targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), and glucocorticoids (GC) in medium and low doses. Monotherapy with methotrexate (MTX), rituximab and combination therapy with bDMARDs +MTX, tsDMARDs+MTX in RA patients reduced the postvaccination pneumococcal response. IgG AT generated in response to PPV23 injection shown functional activity even in RA patients whose antibodies were either lowered in patients receiving MTX or were not detectable at protective values following bDMARD therapy. The potential for pneumococcus antibody production in RA patients receiving therapy with disease-modifying antirheumatic drugs (DMARDs), tsDMARDs and bDMARDs, was concluded. Vaccination against pneumococcal infection should be advised prior to starting therapy due to the likelihood of low antibody levels developing during rituximab treatment.

Immune-Molecular Link between Thyroid and Skin Autoimmune Diseases: A Narrative Review.

Autoimmune skin disorders, including Psoriasis, Lichen Planus, Vitiligo, Atopic Dermatitis, and Alopecia Areata, arise from a combination of genetic predisposition, external factors, and immunological dysfunction. It is well-documented that there is a strong correlation between autoimmune thyroid diseases and a range of dermatological disorders, especially urticaria. This review investigates possible links between autoimmune thyroiditis and a broader spectrum of autoimmune skin conditions, analyzing shared genetic markers, immunological mechanisms, and clinical correlations. Common pathogenic mechanisms include disrupted immune tolerance and oxidative stress, leading to chronic inflammation. Genetic factors, such as IL-23 receptor gene variants, increase the risk for Psoriasis, Alopecia Areata, and Hashimoto's thyroiditis. Additionally, CTLA-4 mutations enhance susceptibility to autoimmune thyroid and skin disorders. Shared genetic susceptibility was also reported in Lichen Planus and Vitilgo, even if different genetic loci might be involved. The breakdown of the immune system can determine a pro-inflammatory state, facilitating the development of autoimmunity and auto-antibody cross-reactions. The presence of similar antigens in skin cells and thyrocytes might explain why both tissues are affected. The significant overlap between these conditions emphasizes the necessity for a comprehensive diagnosis workup and treatment. Future research should focus on clarifying specific immunological pathways and identifying novel biomarkers.

JAK inhibitors inhibit angiogenesis by reducing VEGF production from rheumatoid arthritis-derived fibroblast-like synoviocytes.

JAK/STAT signaling inhibition exerts therapeutic effects on angiogenesis in rheumatoid arthritis (RA). However, whether the inhibitory effect differs among JAK inhibitors because of differing selectivity is unknown. Therefore, we compared the inhibitory effects of tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib on angiogenesis. RA-derived fibroblast-like synoviocytes (RA-FLS) were seeded on type I collagen gel, and human umbilical vein endothelial cells (HUVECs) were directly added. The control and aforementioned JAK inhibitors were added to the medium, followed by stimulation with interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R). Each JAK inhibitor's concentration was determined based on estimated blood concentrations. The vascular endothelial growth factor (VEGF) concentration was evaluated with an enzyme-linked immunosorbent assay using the medium from the first exchange. A migration assay was performed, and HUVEC migration was evaluated using CD31 fluorescence immunostaining. Hematoxylin-eosin staining showed that compared with the non-JAKi treatment group, the JAKi treatment group markedly degenerated in the sub-lining and deep lining, with decreased lymphocyte infiltration and neovascularization [Rooney's score subscale, non-JAKi vs JAKi (median, 6.5 vs 2.5, p = 0.005)]. In vitro, IL-6 and sIL-6R administration increased VEGF production from RA-FLS and promoted neovascularization in HUVECs, and JAK-inhibitor administration, which decreased VEGF production from RA-FLS and suppressed HUVEC migration, inhibited neovascularization in RA-FLS and HUVEC co-cultures. The JAK inhibitors suppressed IL-6-induced angiogenesis via decreased VEGF production and HUVEC migration in RA-FLS and HUVEC co-cultures. No significant differences were observed among the JAK inhibitors, whose anti-angiogenic effect may be an important mechanism for RA treatment. Key Points • JAK inhibitors inhibit angiogenesis in RA by reducing VEGF production from RA-derived fibroblast-like synoviocytes. • Our study provides new insights into RA treatment by elucidating the anti-angiogenic effect of JAK inhibitors.

Analysis of the course and outcomes of COVID-19 at different stages of the pandemic in hemodialysis patients

The purpose of this study was a comparative analysis of the characteristics of the course and outcomes of COVID-19 in HD patients at different stages of the pandemic, focusing on the of the use of immunomodulatory therapy.Materials and methods. The retrospective study included 897 HD patients with COVID-19 (mean age 60.7 years, M 58.5%) who were hospitalized at Moscow City Hospital № 52. Group 1 (n=720) consisted of patients infected between the end of March 2020 and April 2021, group 2 (n=177) included patients hospitalized in May-December 2021. Each of group was divided into 2 subgroups based on treatment approaches. Subgroup 1a (n=231) included patients of the initial period of the pandemic who did not receive adequate immunomodulatory therapy, while Subgroup 1b (n=489) included patients of the late stage, were treated with IL-6 receptor blockers and corticosteroids. In group 2, 108 patients in Subgroup 2a received similar therapy, while 69 patients in Subgroup 2b were treated with neutralizing monoclonal antibodies in the early stages of the disease.Results. Mortality rates in Group 1 and Group 2 was 20.1% and 14.7%, respectively (p<0.09). The incidence of unfavorable outcome was highest in Subgroup 1a and lowest in Subgroup 2b (31.2% vs 5.8%, p<0.01). Mortality in Subgroups 1b and 2a was comparable (14.9% and 20.4%), despite more severe initial lung damage according to CT data in Subgroup 2a. In these patients, immunomodulators was more frequently combined with therapeutic plasma exchange (TPE). Independent risk factors for an unfavorable outcome were the progression of pulmonary pathology, with the transformation of stages CT 1-2 to CT 3-4, and a high comorbidity index.Conclusions. The use of immunomodulatory drugs imprtoved the effectiveness of COVID-19 treatment in patients with CKD5D. In severe cases, the most favorable outcomes were achieved with a combination of immunobiological drugs, corticosteroids, and TPE. An even more significant reduction in mortality was observed following the introduction of neutralizing monoclonal antibodies into clinical practice. Independent predictors of unfavorable outcome of COVID-19 in HD patients were a high comorbidity index and the progression of CT 1-2 into CT 3-4.

Effect of targeted temperature management on systemic inflammatory responses after out-of-hospital cardiac arrest: A prospective cohort study.

Interleukin (IL)-6 is a major inflammatory cytokine that predicts mortality after out-of-hospital cardiac arrest (OHCA). Targeted temperature management (TTM) is associated with improved all-cause mortality in patients with OHCA. However, the effect of TTM on IL-6 production remains unclear. This study investigated whether TTM has additional anti-inflammatory effects after OHCA. This prospective cohort study included a total of 141 hospitalized patients with OHCA who were treated between January 2015 and June 2023. The study was conducted in the intensive care unit of China Medical University Hospital, Taichung. Postcardiac arrest care included TTM or the control approach (no TTM). The primary outcomes included the 90-day mortality rate and neurologic outcomes after OHCA. Differences between the TTM and control groups were examined using Student t test, chi-square test, and Kaplan-Meier survival curve analysis. Multivariate analysis of variance model was used to examine interaction effects. Plasma IL-6 and IL-6/soluble IL-6 receptor complex levels were measured at 6 and 24 hours after resuscitation. IL-6 and IL-6/soluble IL-6 receptor complex production was lower in the TTM group than in the control group (-50.0% vs +136.7%, P < .001; +26.3% vs +102.40%, P < .001, respectively). In addition, the 90-day mortality rate and poor neurologic outcomes were lower in the TTM group than in the control group (36.8% vs 63.0%, relative risk 0.39, 95% confidence interval 0.24-0.64, P < .001; 65.5% vs 81.5%, relative risk 0.80, 95% confidence interval 0.66-0.98, P = .04). TTM improves both the mortality rate and neurologic outcomes in patients resuscitated from OHCA, possibly by reducing IL-6-induced proinflammatory responses.

Brainstem transcriptomic changes in male Wistar rats after acute stress, comparing the use of duplex specific nuclease (DSN)

In this work, we have analyzed the transcriptomic changes in the brainstem of male Wistar rats 2 h after an acute stress exposure. We performed duplex-specific nuclease normalization of cDNA libraries and compared the results back-to-back for the first time. Based on our RNAseq data, we selected reference genes for RT-qPCR that are best suited for acute stress experiments. Most genes were upregulated. We detected a massive shift in neuropeptide Crh, Trh,Cga, Tshb, Uts2b, Tac4, Lep and neuropeptide receptor Hcrtr1, Sstr5, Bdkrb2, Crhr2 signaling, as well as glutamate Grin3b, Grm2 and GABA Gpr156, acetylcholine Chrm4,Chrne, adrenergic Adra2b receptors expression. A strong increase in the expression of intermediate filaments Krt83/Krt86/Krt80/Krt84/Krt87/Krt4/Krt76 and motor proteins Myo7a, Klc3 was detected. Remarkably, in the absence of astrocyte activation, we also observed signs of microglial activation at this time point. Both expression of anti-inflammatory cytokines Il13, Ccl24 and pro-inflammatory cytokine receptors Il9r, Il12rb1, Tnfrsf14, Tnfrsf13c, Tnfrsf25, Tnfrsf1b were increased. In the Wnt signaling pathway, we observed increased expression of ligands-receptors Wnt1, Wnt11, Ror2 and also negative regulators Notum, Sfrp5, Sost. RNAseq results after DSN treatment correlated at a high level with RNAseq results without DSN, but there was a proportion of genes that shifted their logFC values. They are mostly rare transcripts TPM 1–10 with higher 0.5–0.9 GC content.

Mechanistic and dynamic insight into novel IL7 receptor activators as immunotherapy for the treatment of tuberculosis

The bacterium that causes tuberculosis (TB), Mycobacterium tuberculosis, is still a significant global public health problem due to its contagious nature and the emergence of drug-resistant variants. This study leverages network pharmacology and computational drug discovery to identify genes linked to TB using the GSE54992 and GSE62525 datasets. In active tuberculosis patients, it identifies 162 DEGs that are not present in healthy people. The research includes an investigation of gene ontology (GO) and protein–protein interaction (PPI) networks to provide a comprehensive understanding of these DEGs. Crucially, it identifies ten hub genes: IL7R, CCR7, CXCR5, CCR6, CCR9, S1PR1, BACH2, CXCL5, SPIB, and EBF. The research suggests IL7R as a potential therapeutic target because of its essential role in FoxO signalling pathways and cytokine-cytokine receptor interaction. IL7 and its receptor (IL7R) are vital for T cell functionality and essential in combating TB. The study explores novel small-molecule activators for IL7R (IL7Rα), aiming to boost the immune response against TB. The following four compounds were found using molecular dynamics simulation, virtual screening, computational pharmacophore modelling, and MM/GBSA analytical techniques: ZINC02131028, ZINC02135418, ZINC46007405, and ZINC59273354. These activators may enhance the IL7 signalling pathway, potentially strengthening the immune fight against M. tuberculosis. Among these ZINC02131028 showed the best results to activate IL7 by binding to its active site, stabilizing its active conformation and enhancing its interaction with the IL7 receptor (IL7R). The findings encourage experimental validation of these IL7 activators, marking a significant step towards innovative TB treatment strategies.

Dissecting depression symptoms: Multi-omics clustering uncovers immune-related subgroups and cell-type specific dysregulation

In a subset of patients with mental disorders, such as depression, low-grade inflammation and altered immune marker concentrations are observed. However, these immune alterations are often assessed by only one data type and small marker panels. Here, we used a transdiagnostic approach and combined data from two cohorts to define subgroups of depression symptoms across the diagnostic spectrum through a large-scale multi-omics clustering approach in 237 individuals. The method incorporated age, body mass index (BMI), 43 plasma immune markers and RNA-seq data from peripheral mononuclear blood cells (PBMCs). Our initial clustering revealed four clusters, including two immune-related depression symptom clusters characterized by elevated BMI, higher depression severity and elevated levels of immune markers such as interleukin-1 receptor antagonist (IL-1RA), C-reactive protein (CRP) and C-C motif chemokine 2 (CCL2 or MCP-1). In contrast, the RNA-seq data mostly differentiated a cluster with low depression severity, enriched in brain related gene sets. This cluster was also distinguished by electrocardiography data, while structural imaging data revealed differences in ventricle volumes across the clusters. Incorporating predicted cell type proportions into the clustering resulted in three clusters, with one showing elevated immune marker concentrations. The cell type proportion and genes related to cell types were most pronounced in an intermediate depression symptoms cluster, suggesting that RNA-seq and immune markers measure different aspects of immune dysregulation. Lastly, we found a dysregulation of the SERPINF1/VEGF-A pathway that was specific to dendritic cells by integrating immune marker and RNA-seq data. This shows the advantages of combining different data modalities and highlights possible markers for further stratification research of depression symptoms.

Piecing Together the Role of IL-4 Receptor Alpha in Allergic Asthma One Cell at a Time.

Piecing Together the Role of IL-4 Receptor Alpha in Allergic Asthma One Cell at a Time.

Abstract A047: Fibroblast-specific IL1 receptor inhibition reprograms the inflammatory stroma to overcome the immunosuppressive tumor microenvironment in pancreatic cancer

Abstract OBJECTIVE: KRAS-driven inflammatory signaling in pancreatic ductal adenocarcinoma (PDAC) promotes cancer-associated fibroblast (CAF) polarization and an immunosuppressive tumor microenvironment (iTME), driving therapeutic resistance. IL1α, a downstream product of KRAS signaling, activates the pro-inflammatory CAF (iCAF) phenotype and correlates with worse survival. Using patient and PDAC mouse model single-cell RNA sequencing (scRNAseq) data, we have shown that the IL1 Receptor (IL1R1) is highly enriched in the fibroblast compartment. However, the role of IL1R1 in modulating iCAFs and the iTME remains poorly understood. We hypothesize that CAF-specific disruption of IL1R1 signaling will reprogram cellular components of the PDAC TME to overcome the immunosuppressive milieu and therapeutic resistance. METHODS: The effects of IL1R1 inhibition on iCAF modulation in vivo were determined in Ptf1aCre/+, LSL-KrasG12D/+, Tgfbr2flox/flox (PKT) mice treated with IL1R1 antagonist. To determine if CAF-specific silencing of IL1R1 recapitulates the TME remodeling after IL1R1 inhibition, we generated a fibroblast-specific IL1R1KO mouse model Col1a2Cre/+;Il1r1flox/flox (CAF-Il1r1KO) and orthotopically injected KPC tumor cells for endpoint analysis. Flow cytometry was performed in primary tumors of CAF-Il1r1KO and littermate controls. Functional experiments evaluating myeloid-derived suppressor cell (MDSC) trafficking were performed using ex vivo bone marrow-derived cells (BMDCs) co-cultured with CAF/tumor-conditioned media (CM) with/without IL1R1 inhibition in a transwell system. MDSC contribution to iTME was assessed by co-culturing MDSCs from CAF-Il1r1KO tumors and splenic T cells from naïve C57BL/6 mice. To investigate the effects of IL1R1 deletion in overcoming therapeutic resistance, survival studies in CAF-Il1r1KO mice with chemotherapy were conducted. RESULTS: Treatment of PKT mice with IL1R1 antagonist diminished transcriptional levels of Il6 and Cxcl1, iCAF-associated cytokines, in the CAF compartment. Compared to littermate controls, orthotopic tumors in CAF-Il1r1KO showed significant reduction in tumor weights, increased CD8+ T cell infiltration, and overall reduction in polymorphonuclear (PMN) MDSC trafficking by flow cytometry. Moreover, migration of BMDCs was reduced when co-cultured with CAF/tumor CM and IL1R1 antagonist. In addition, co-culture of MDSCs from CAF-Il1r1KO mice with naïve T cells showed diminished inhibition of T cell functional activity. Chemotherapy treatment of orthotopic tumors in CAF-Il1r1KO mice showed significantly decreased tumor size and improved survival compared to tumors in littermate controls. CONCLUSION: Our findings illustrate a novel mechanism of CAF-specific disruption of IL1R1 signaling inhibiting trafficking of immunosuppressive MDSCs and increased infiltration of cytotoxic CD8+ T cells in the PDAC TME. These data pave the way for novel combinatorial treatment strategies targeting IL1R1 to overcome chemotherapeutic resistance through reprogramming of the stromal compartment in PDAC. Citation Format: Camille Acevedo, Samara Singh, Austin Dosch, Edmond W Box, Iago C Silva, Anna Bianchi, Siddharth Mehra, Haleh Amirian, Andrew Adams, Nagaraj Nagathihalli, Jashodeep Datta, Nipun B Merchant. Fibroblast-specific IL1 receptor inhibition reprograms the inflammatory stroma to overcome the immunosuppressive tumor microenvironment in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A047.

A Pooled Analysis of Eight Clinical Studies Suggests a Link Between Influenza-Like Symptoms and Pharmacodynamics of the Toll-Like Receptor-7 Agonist Vesatolimod.

Vesatolimod is a Toll-like receptor-7 (TLR7) agonist in clinical development as part of a combination regimen for human immunodeficiency virus (HIV) cure. Influenza-like symptoms associated with TLR7-mediated immune activation have been reported in clinical trials of vesatolimod. Therefore, a broader understanding of the safety profile of vesatolimod and association with dose and mechanism of action will help inform future clinical studies. In this analysis, data on flu-like adverse events of interest (AEIs) were pooled from eight clinical studies in which 606 participants either received single or multiple doses of vesatolimod (0.3-12mg; n = 505) or placebo (n = 101). Vesatolimod pharmacokinetics, inflammatory responses, and pharmacodynamics were assessed. The incidence of flu-like AEIs was higher with vesatolimod versus placebo (19% [96/505] vs. 8% [8/101]) and increased with vesatolimod dose and exposure. Most flu-like AEIs with vesatolimod were grade 1 or 2 severity (55% [53 of 96] grade 1; 35% [34 of 96] grade 2) with onset primarily after the first and second dose. Occurrence of flu-like AEIs after doses 1-3 was predictive of reoccurrence after later doses. Dose-dependent elevations of pharmacodynamic biomarkers (interferon-stimulated gene 15, 2'-5'-oligoadenylate synthetase 1, myxovirus resistance-1, interferon-α, interleukin-1 receptor antagonist, interferon-γ-induced protein 10, interferon-inducible T-cell-α chemoattractant) observed in participants with flu-like AEIs suggest a link with vesatolimod mechanism of action. Flu-like AEIs associated with vesatolimod administration were typically mild but increased with exposure, which may be predicted by the response to initial doses. The data suggest that adaptive clinical monitoring could help maximize pharmacodynamic responses and balance adverse events in future clinical trials of vesatolimod.

Abstract B057: The circadian master regulator BMAL1 blocks immune cell recognition of pancreatic ductal adenocarcinomas via tumor-derived interleukin-1 receptor antagonist

Abstract Many tumor types, including pancreatic adenocarcinomas, have dysregulated circadian rhythms. Previous work in our lab has shown that disseminated dormant tumor cells have increased expression of Dec2, a circadian rhythm gene, and knocking out Dec2 leads to increased overall survival in our murine resectable PDAC model. To see whether the effect of Dec2 is due to a circadian effect, we deleted the master regulator circadian gene, BMAL1. Using CRISPR-generated knockout (KO) cell lines, we saw that loss of Bmal1 completely abrogated metastasis in immunocompetent mice, but not in immunocompromised mice indicating an immune mediated mechanism. Similarly in our murine resectable PDAC model, loss of BMAL1 led to an increase in overall survival in immunocompetent mice only. Looking at the tumor microenvironment, we saw an increase in CD4+ and CD8+ T cell infiltration in the tumors derived from the BMAL KO cells. We then evaluated the BMAL KO cells for their cytokine secretion and saw that loss of BMAL1 led to decreased interleukin-1 receptor antagonist both in vitro and in vivo. IL-Ra has been shown in literature to suppress the immunogenic anti-tumor response by impairing the activities of APCs, CD4+ and CD8+ T cells and disruption of IL-1Ra can reverse the TME towards more immunogenic leading to an antitumor effect. Taken together these studies implicate Bmal1 in regulating anti-tumor immunity in PDAC through its regulation of IL-1Ra secretion. This is a novel function for a circadian rhythm gene in PDAC biology. Citation Format: Orjola Prela, Lan Wang, Chris Harris, Darren Carpizo. The circadian master regulator BMAL1 blocks immune cell recognition of pancreatic ductal adenocarcinomas via tumor-derived interleukin-1 receptor antagonist [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B057.

Abstract A051: Innate immune cell dynamics and pancreatic tumor progression in alcoholic pancreatitis

Abstract Introduction: Persistent inflammation due to alcoholic chronic pancreatitis (ACP) is associated with pancreatic ductal adenocarcinoma (PDAC). Myeloid cell infiltration within the pancreas, particularly with oncogenic mutant KrasG12D/+ (*Kras), is crucial for driving PDAC carcinogenesis. Our previous work demonstrated that hyperactivation of cyclic AMP response element binding protein (CREB) accelerates ADM/PanIN progression with heightened fibroinflammation. However, the association between CREB in precursor neoplastic lesions and innate myeloid cells remains unclear. Methods: We established an ACP mouse model using an alcohol diet along with prolonged caerulein administration in Ptf1aCreERTM/+; LSL-KrasG12D/+ (KC), and CREB deleted [Crebfl/fl in KC (KCC-/-)] mice. Single-cell RNA sequencing (scRNA-seq) of the mouse pancreas, multiparametric immunophenotyping of tumor-infiltrating myeloid cells and chromatin immunoprecipitation (ChIP-seq) with CREB pulldown were performed. Cytokine arrays and qPCR studies followed co-culture assays using mouse neutrophils (J774M) and macrophages (RAW 264.7) with epithelial cell lines harboring *Kras with in vitro ACP induction were conducted. Results: ACP induction in KC mice led to increased infiltration of neutrophils and alternatively activated macrophages with the pancreas. Conversely, Creb-deleted mice exhibited significantly reduced myeloid cell infiltration despite ACP induction. ChIP-Seq and qPCR identified CREB-regulated chemokines and immunomodulators as mediators of myeloid cell trafficking. Co-culture of mouse neutrophils and macrophages with KC-ACP conditioned media significantly increased IL-1 receptor antagonist (Il-1ra) expression and secretion. Single-cell transcriptomic analysis revealed heightened Il1rn mRNA levels in neutrophils and macrophages in KC-ACP when compared with KC pancreatic tumors. Creb-deleted PDAC models showed strong downregulation of Il1rn in macrophages, confirming CREB’s role in modulating myeloid cell interactions via epithelial cell signaling. Conclusions: Our findings highlight that CREB activation in epithelial cells under ACP conditions facilitates crosstalk with myeloid cells, promoting IL-1ra upregulation in neutrophils and macrophages. This CREB-driven regulation of IL-1ra in myeloid cells contributes to inflammation-associated tumorigenesis. Targeting this axis may offer a novel therapeutic approach to curb pancreatic cancer progression. Citation Format: Siddharth Mehra, Sudhakar Jinka, Varun Krishnamoorthy, Supriya Srinivasan, Anna Bianchi, Andrew Adams, Haleh Amirian, Manan Patel, Jashodeep Datta, Nipun Merchant, Nagaraj Nagathihalli. Innate immune cell dynamics and pancreatic tumor progression in alcoholic pancreatitis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A051.