Uncovering the complex role of interferon-gamma in suppressing type 2 immunity to cancer

Cytokine, Год журнала: 2023, Номер 171, С. 156376 - 156376

Опубликована: Сен. 23, 2023

Язык: Английский

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Inhibition of NETs prevents doxorubicin-induced cardiotoxicity by attenuating IL-18-IFN-γ-Cx43 axis induced cardiac conduction abnormalities

International Immunopharmacology, Год журнала: 2025, Номер 147, С. 114016 - 114016

Опубликована: Янв. 12, 2025

Язык: Английский

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Immune checkpoints and cancer immunotherapies: insights into newly potential receptors and ligands

Therapeutic Advances in Vaccines and Immunotherapy, Год журнала: 2023, Номер 11

Опубликована: Янв. 1, 2023

Checkpoint markers and immune checkpoint inhibitors have been increasingly identified developed as potential immunotherapeutic targets in various human cancers. Despite valuable efforts to discover novel checkpoints their ligands, the precise roles of therapeutic functions, well broad identification counterpart receptors, remain be addressed. In this context, it has suggested that putative receptors can induced upon activation. tumor microenvironment, T cells, crucial response against malignant diseases other central effector such natural killer are regulated via co-stimulatory or co-inhibitory signals from cells. Studies shown exposure cells antigens upregulates expression inhibitory leading T-cell dysfunction exhaustion. Although targeting regulators relative clinical efficacy some types, most trials field cancer immunotherapies revealed unsatisfactory results due de novo adaptive resistance patients. To overcome these obstacles, combinational therapies with newly discovered molecules combined blockage several provide a rationale for further research. Moreover, counterparts at is likely promise effective therapies. review, we examine prospects application emerging checkpoints, immunoglobulin mucin domain 3, lymphocyte activation gene-3, immunoreceptor Ig ITIM domains (TIGIT), V-domain suppressor (VISTA), new B7 family proteins, B- attenuator, association immunotherapy malignancies. addition, biological significance discussed, including cancers, along T-cell-mediated responses.

Язык: Английский

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Enhancing Dendritic Cell Activation Through Manganese-Coated Nanovaccine Targeting the cGAS-STING Pathway

International Journal of Nanomedicine, Год журнала: 2024, Номер Volume 19, С. 263 - 280

Опубликована: Янв. 1, 2024

Background: Nanovaccines have emerged as a promising vaccination strategy, exhibiting their capacity to deliver antigens and adjuvants elicit specific immune responses. Despite this potential, optimizing the design delivery of nanovaccines remains challenge. Methods: In study, we engineered dendritic mesoporous silica-based nanocarrier enveloped in metal-phenolic network (MPN) layer containing divalent manganese ions tannic acid (MSN@MT). This was tailored for antigen loading serve nanovaccine, aiming activate cyclic GMP-AMP synthase-stimulator interferon genes (cGAS-STING) pathway cells (DCs). Our experimental approach encompassed both cellular assays mouse immunizations, allowing comprehensive evaluation nanovaccine's impact on DC activation its influence generation antigen-specific T-cell Results: MSN@MT demonstrated remarkable enhancement humoral responses mice compared control groups. highlights potential effectively trigger cGAS-STING DCs, resulting robust Conclusion: study introduces MSN@MT, unique incorporating acid, showcasing exceptional ability amplify by activating DCs. innovation signifies stride refining nanovaccine potent activation. Keywords: nanocarrier, network, ions,

Язык: Английский

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Phosphorylation of AQP4 by LRRK2 R1441G impairs glymphatic clearance of IFNγ and aggravates dopaminergic neurodegeneration

npj Parkinson s Disease, Год журнала: 2024, Номер 10(1)

Опубликована: Янв. 31, 2024

Abstract Aquaporin-4 (AQP4) is essential for normal functioning of the brain’s glymphatic system. Impaired function associated with neuroinflammation. Recent clinical evidence suggests involvement dysfunction in LRRK2 -associated Parkinson’s disease (PD); however, precise mechanism remains unclear. The pro-inflammatory cytokine interferon (IFN) γ interacts to induce Therefore, we examined AQP4-dependent system’s role IFNγ-mediated neuroinflammation PD. We found that and phosphorylates AQP4 vitro vivo. phosphorylation by R1441G induced depolarization disrupted IFNγ clearance. Exogeneous significantly increased astrocyte expression receptor, amplified depolarization, exacerbated transgenic mice. Conversely, inhibiting restored polarity, improved function, reduced dopaminergic neurodegeneration. Our findings establish a link between LRRK2-mediated PD, guiding development targeting therapy.

Язык: Английский

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Hemophagocytic lymphohistiocytosis: current treatment advances, emerging targeted therapy and underlying mechanisms

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Ноя. 7, 2024

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as complex cytokine storm. This hyperactive response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements its treatment. The storm plays crucial role treatment of HLH. Investigating detailed mechanisms behind storms offers insights into targeted therapeutic approaches, potentially aiding early intervention improving clinical outcome patients. To date, only one therapy, emapalumab targeting interferon-γ, that gained approval for primary review aims summarize current advances, emerging therapeutics underlying HLH, highlighting newly discovered targets involved storms, which are expected drive development novel treatments offer fresh perspectives future studies. Besides, multi-targeted combination therapy may be essential disease control, but further trials required determine optimal mode

Язык: Английский

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Revisiting immune checkpoint inhibitors: new strategies to enhance efficacy and reduce toxicity

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Дек. 10, 2024

In recent years, ICIs have transformed cancer treatment by harnessing the body's immune system to target and destroy cells [1][2][3]. work blocking inhibitory signals that prevent T from attacking tumors, thereby reactivating response against cancer. The most common targets for these therapies are PD-1/PD-L1 CTLA-4 pathways, which critical in regulating responses [4]. By inhibiting drugs like nivolumab, pembrolizumab, ipilimumab shown remarkable efficacy treating cancers such as melanoma, non-small cell lung (NSCLC), renal carcinomaFor example, a PD -1 inhibitor, has been breakthrough of melanoma. large -scale clinical trial involving patients with advanced nivolumab led significant improvement overall survival, approximately 40% surviving more than five years compared less 20% traditional chemotherapy [5]. Pembrolizumab, another non -small (NSCLC). phase III trial, it demonstrated an objective rate around -30% previously treated since incorporated into first -line regimens, improving survival outcomes quality life many [6]. Ipilimumab, CTLA -4 had transformative impact on metastatic It was drug show benefit this difficult -to -treat cancer, increasing median time several months providing new option limited alternatives [7,8]. While range cancers, including melanoma their potential bone tumors remains underexplored. Addressing gap, article also considers strategies tailored enhance ICI specifically tumor casesThese examples clearly illustrate success different types ability revolutionize treatment. underexplored.Addressing cases.These particularly revolutionary were treat, offering long-term remission some patients. However, despite successes, not universally effective. Many do respond treatment, those who may develop resistance over [9]. Additionally, activation can lead severe immune-related adverse events (irAEs), affect various organs require careful management [10]. challenges suboptimal toxicity highlight need refined use ICIs. Personalized approaches, combination therapies, development next-generation improved specificity safety profiles essential maximizing therapeutic treatments.Despite ICIs, is accompanied challenges.One foremost issues variable among individuals experience dramatic long-lasting regression, others at all, phenomenon known primary Even responders, subset acquired time, leading progression after initial period [11].Another challenge occurrence irAEs. These toxicities arise multiple organs, skin, gastrointestinal tract, liver, endocrine [12]. IrAEs mild be life-threatening, necessitating immunosuppressive treatments might diminish anti-tumor [13]. Furthermore, high cost presents barrier access, limiting availability broader patient populationAdditionally, major hurdle. Primary resistance, where start, attributed factors. Tumors low immunogenicity, due lack -specific antigens or suppressive microenvironment rich regulatory (Tregs) myeloid -derived suppressor (MDSCs), effective infiltration [14]. Genetic alterations within cells, mutations interferongamma pathway genes, [15]. Acquired develops initially responsive patients, involve upregulation alternative checkpoint TIM -3 LAG -3, compensate blocked -1/PD -L1 pathways [16]. Tumor adapt losing expression developing mechanisms evade recognition, through antigenpresentation machinery defects [17]. Understanding underlying crucial sets stage later discussion emerging overcome resistance. population [18]. underscore urgent predict response, manage toxicity, reduce costs, optimizing application therapy.ICIs targeting become integral modern therapy [19,20]. PD-1 inhibitors, interaction between its ligand PD-L1 reinvigorating attack [21]. inhibitors substantial carcinoma. Similarly, dampen responses, context [22]. Despite all therapies. Response rates vary significantly, being resistant factors, genetic [23]. Bone osteosarcoma, present unique immunotherapy complex [24]. This explores how approaches could potentially barriers, while outlook they curative portion eventually [25]. limitations ongoing research refine improve rates.The introduction marked advancement therapy, but associated distinct set Unlike chemotherapy-induced toxicities, irAEs result overactivation begins only healthy tissues [26]. almost any organ system, commonly impacted glands [27].Dermatologic rash pruritus, frequent irAEs, often appearing early [28]. Gastrointestinal colitis diarrhea, severe, life-threatening complications if promptly managed [29]. Hepatotoxicity, manifesting elevated liver enzymes hepatitis, concern requires monitoring sometimes cessation [30]. Endocrine thyroiditis, adrenal insufficiency, hypophysitis, hormonal imbalances, hormone replacement therapy. Pulmonary pneumonitis, life-threatening. Cardiovascular neurological though rare, occur pose serious risks.The involves corticosteroids other immunosuppressants mitigate [31]. approach compromise creating delicate balance controlling maintaining benefit. unpredictability nature close monitoring, intervention, selective minimize off-target effects. As continues expand, understanding managing will outcomes.Biomarker-guided represents promising enhancing tailoring characteristics each patient's [32]. Biomarkers expression, mutational burden (TMB), microsatellite instability (MSI) identified predictors For better making factor selection acknowledged factors influence instance, presence microenvironment, Tregs MDSCs, [33]. interferon -gamma sensitivity even levels [34]. Therefore, comprehensive evaluation takes account accurate prediction.Similarly, burden, reflects number tumor's DNA, correlated increased neoantigen formation, system's recognize [35]. Microsatellite instability, condition hypermutability, serves biomarker colorectal [36].By utilizing biomarkers, clinicians accurately identify likely thus outcomes. Currently, there efforts standardize assessment biomarkers. Several professional organizations consortia working towards establishing unified testing methods criteria evaluation. includes standardizing assays used measure TMB, MSI, well defining cut -off values determining positivity [37][38][39].Standardization would reproducibility generalizability -guided strategies. If laboratories clinics inconsistent methods, varying results inaccurate selection. With standardized assessment, reliability -based decisions improve, allowing implementation personalized medicine focused discovering biomarkers refining existing ones, future.Combination emerged powerful strategy [40]. combining modalities, chemotherapy, targeted radiotherapy, possible achieve robust durable [41]. rationale behind combinations lies synergistic effects achieved when complementary involved growth evasion.For radiotherapy induce immunogenic death, increases release enhances subsequent paired [42]. Targeted angiogenesis specific oncogenic modify susceptible immunemediated destruction. simultaneously block checkpoints, tumor.Recent trials showing extended monotherapy [43]. challenges, complexity [44]. continued exploration holds promise adequately alone.Optimizing dosing scheduling minimizing toxicities. Traditional regimens fixed doses schedules individual variability metabolism [45]. Emerging evidence suggests strategies, intermittent dose reductions, maintain reducing risk allow tolerable comorbidities lower tolerance treatment.In addition optimization, adjusting timing administration explored way administering conjunction treatments, intervals taking advantage immunomodulatory [46]. relation circadian rhythms cycles area active research, further optimal results. represent avenues effectiveness therapy.Selective engineering [47]. effective, broad system. To address this, researchers nextgeneration designed precisely sparing tissues.One enhanced affinity tumor-specific altered proteins predominantly expressed microenvironment. reduces minimizes higher without [48].In selectivity, advances protein enabling creation optimized pharmacokinetics pharmacodynamics [49]. engineered longer half-lives, greater stability, controlled activation, dosing. bispecific antibodies two checkpoints combine inhibition immune-stimulating functions increase potency innovations paving safer immunotherapies, hope benefited treatments.Immune modulation aim preserving [50]. One agents excessive cause blunt desired activation. Researchers exploring modulators selectively compromising [51].In pharmacological interventions, modulate effectively. promote immune-regulating extent [52].These still stages hold tolerable, side effects.Effective components inhibitor (ICI) Given systems, detection intervention complications. Routine receiving should include regular assessments symptoms, laboratory tests, imaging studies detect [53]. Early identification allows prompt management, adjustments, temporary discontinuation initiation control inflammation.A multidisciplinary required diverse Involvement specialists, endocrinologists, gastroenterologists, pulmonologists, help [54]. education plays role aware signs symptoms importance reporting them healthcare team. proactive communication earlier interventions outcomes.Long-term essential, late course ended. Continued follow-up ensures delayed appropriately health maintained.By integrating protocols approach, maximize benefits risks, ultimately therapy.In article, we explore aimed biomarker-guided scheduling, summarized Table 1. table provides concise overview key intended outcomes, illustrating both Enhanced ICIs.Maximizing schedules.Minimized designing antigens, reduced irAEs.Balancing suppression corticosteroids, modulators, strategic ICIs.The future overcoming current expanding treatments. offer selectivity [55]. Advances biotechnology antibodies, molecules, novel provide broaden applicability wider currently therapies.In development, ICIsImportantly, positive -effectiveness developed, lines costlier. ensure prescribed benefit, avoiding unnecessary costs -responders. [56]. identifying molecular contribute restore integration practice ensuring receive based characteristics.Another direction sequencing Optimizing evolve, growing interest non-cancer indications, opening frontiers autoimmune diseases chronic infections. Together, shape cornerstone precision oncology.In summary, revolutionized presenting limitations. Ongoing dosing, ICIs.By effectively integrated patients.The hinges collaborative researchers, clinicians, industry leaders. fully realize prioritize mechanisms, precise profiles. Clinicians must adopt training professionals stay informed about latest advancements fostering innovation, collaboration, education, oncology community accessible beneficial act now, refinement shaping treatment.The refinements poised significantly continue aspects biology. promises expand enable safely developments pave paradigms focus disease increasingly rely comprehensive, patient-specific life.

Язык: Английский

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Exploratory study on the efficacy of topical pan-JAK inhibitor in ocular and skin GVHD in a sclerodermatous GVHD mouse model

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 2, 2025

Systemic administration of Janus kinase (JAK) inhibitors is effective in treating chronic graft-versus-host disease (cGVHD) but associated with side effects. Topical drug effectively minimizes We aimed to investigate potential trends the efficacy topical delgocitinib a mouse model. Allogenic bone-marrow transplantation (BMT) was performed from B10.D2. BALB/c mice, leading sclerodermatous GVHD. GVHD mice were treated eye drops or ointment samples analyzed at 4 weeks post-BMT. and eye-drop significantly increased meibomian gland (MG) area attenuated corneal epithelial damage. Pathological immunohistochemical analyses revealed substantial reduction inflammation pathological fibrosis skin eyelids delgocitinib-treated mice. Signal transducer activator transcription (STAT)1, STAT3, STAT5A phosphorylation back vehicle-treated mice; reduced expression these phosphorylated STAT molecules. Delgocitinib damage, MG acinar depletion, inflammatory cells infiltration corneas. The JAK/STAT signaling pathway upregulated In summary, our data suggested that had attenuate cGVHD phenotype severity eyes

Язык: Английский

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Ganoderma atrum polysaccharide interferes with TLR4 against PD-1 inhibitors-induced carditis via NF-κB-NLRP3 pathway driven by IRF1/VEGFA/14–3-3γ axis in Lewis lung carcinoma mice

Journal of Functional Foods, Год журнала: 2025, Номер 127, С. 106732 - 106732

Опубликована: Март 23, 2025

Язык: Английский

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The role of interferon-gamma and its receptors in gastrointestinal cancers

Pathology - Research and Practice, Год журнала: 2023, Номер 248, С. 154636 - 154636

Опубликована: Июнь 21, 2023

Язык: Английский

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