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关键词： IL-21   Radiotherapy   Melanoma   Anti-tumor  

摘要： Melanoma, known for its aggressive behavior and tendency to metastasize to the brain and lungs, is a formidable challenge in oncology. Radiotherapy is a potent treatment for localized solid tumors, effective against both intracranial and extracranial metastases. Yet, some melanoma patients exhibit substantial resistance to radiotherapy, with the underlying mechanisms of this resistance remaining elusive. While radiotherapy can stimulate the infiltration of immune cells, thereby triggering a range of immunostimulatory effects, it can also suppress the tumor microenvironment (TME), limiting its effectiveness. In physiological conditions, cytokines inhibit the activity of immunosuppressive cells through paracrine and autocrine signaling, while also activating immune cells to boost antitumor responses. Here, we found that Interleukin (IL)-21 expression was higher in the mice with good radiotherapy response to melanoma than in the mice with poor radiotherapy response. Interestingly, we also observed the higher infiltration of M2 TAMs and lower CD8+ T cells in the group with poor radiotherapy response. To tackle this issue, we explored the therapeutic potential of a plasmid encoding IL-21, delivered via attenuated Salmonella, in mice bearing melanomas. Our findings revealed that IL-21 administration significantly reduced M2 TAMs infiltration and enhanced CD8+ T cells infiltration and granzyme B (GZMB) expression within melanoma tumors. Most importantly, the combination of IL-21 with radiotherapy led to markedly tumor reduction compared to either treatment alone. This research highlights the potential of IL-21 as a valuable adjunct to radiotherapy in the treatment of melanoma, presenting a promising strategy for enhancing antitumor immune responses and optimizing patient outcomes.

关键词： Breast cancer   P18   interleukin 24   fusion protein   molecular docking   MD simulations  

摘要： Breast cancer is the second leading cause of cancer-related deaths throughout the world, and it remains one of the significant health challenges due to treatment limitations such as drug resistance and adverse side effects. Instead of developing novel treatment approaches, including radiotherapy and chemotherapy, their efficacy is trapped by non-specific toxicity and resistance. This study includes designing a novel chimeric protein combining Interleukin-24 (IL-24) and p18 peptides that are well-being to exhibit significant anticancer properties. The fusion protein, IL-24-P18, was developed to enhance specificity and minimize off-target effects in breast cancer treatment. We used silico techniques to predict this novel fusion protein construct's structural, functional and therapeutic properties. The P18 peptide was fused to the N-terminal of IL-24 using an AEAAAKEAAAKA linker. The fusion protein was found to be nontoxic, non-allergenic and non-antigenic. The fusion protein was hydrophilic with a neutral charge, exhibiting soluble expression in E. coli and stable at varying conditions. Secondary and tertiary structure predictions showed well-defined alpha-helices and a stable 3D conformation. Molecular docking and interaction analysis further confirmed strong binding affinities with a score of -847.5 Kcal/mol between IL-24-P18 and breast cancer receptor proteins, indicating the potential for selective targeting. Moreover, the MD simulation results revealed the interaction stability of the designed fusion protein and receptor. The overall results of this Insilco study showed that IL-24-P18 fusion is a prospective novel candidate against breast cancer that has the potential to inhibit breast cancer with higher accuracy and fewer side effects as compared to already available treatments. Further, in vitro and clinical studies are required to validate its clinical applicability.

关键词： Cancer   Cytokines   Hematology   Immunotherapy   Transplantation  

摘要： BACKGROUND. The graft-versus-leukemia (GVL) effect contributes to the efficacy of allogeneic stem cell transplantation (alloSCT). However, relapse, indicative of GVL failure, is the greatest single cause of treatment failure. Based on preclinical data showing that IFN-gamma is important to sensitize myeloblasts to alloreactive T cells, we performed a phase I trial of IFN-gamma combined with donor leukocyte infusions (DLIs) in myeloblastic malignancies that relapsed after HLA-matched alloSCT. METHODS. Patients with relapsed acute myeloid leukemia or myelodysplastic syndrome after alloSCT were eligible. Patients self-administered IFN-gamma for 4 weeks (cohort 1) or 1 week (cohort 2), followed by DLI and concurrent IFN-gamma for a total of 12 weeks. Bone marrow samples were analyzed by single-cell RNA sequencing (scRNA-Seq) to assess in vivo responses to IFN-gamma by malignant myeloblasts. RESULTS. IFN-gamma monotherapy was well tolerated by all participants (n = 7). Treatment-related toxicities after DLI included grade I-II graft-versus-host disease (n = 5), immune effector cell-associated neurotoxicity syndrome (n = 2), and idiopathic pulmonary syndrome (n = 1), all of which resolved with corticosteroids. Four of 6 DLI recipients achieved minimal residual disease-negative complete remissions and full donor hematopoietic recovery. Median overall survival was 579 days (range, 97-906) in responders. scRNA-Seq validated in vivo activation of the IFN-gamma response pathway in hematopoietic stem cell-like or myeloid progenitor cells after IFN-gamma in analyzed samples. CONCLUSION. IFN-gamma was safe and well tolerated in this phase I study of IFN-gamma for relapsed acute myeloid leukemia and myelodysplastic syndrome after alloSCT, with a promising efficacy signal when combined with DLI. Larger studies are needed to formally test the efficacy of this approach. TRIAL REGISTRATION. *** NCT04628338.

关键词： alopecia areata   brodalumab   erythroderma   IL-17C   pityriasis rubra pilaris  

关键词： Palmoplantar pustulosis   IL-23 inhibitors   guselkumab   risankizumab   small-molecule inhibitors   apremilast   clinical trials  

摘要： Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterized by recurrent pustules, erythema, and scaling on the palms and soles, leading to a significantly reduced quality of life. Although PPP shares some immunopathological features with psoriasis vulgaris, it is distinguished by unique genetic predispositions, including a higher prevalence in East Asian populations, and a complex immune profile, particularly dysregulation of the IL-23/Th17 axis and IL-36 cytokines. Recent advances in psoriasis treatment have highlighted IL-23 inhibitors, which target the p19 subunit to suppress Th17 activation and inflammatory cytokines. Clinical trials show that IL-23 inhibitors significantly improve disease severity and patient-reported outcomes in PPP while maintaining favorable safety profiles. Notably, guselkumab and risankizumab have recently been approved for PPP treatment in Japan and Korea. In contrast, IL-17 inhibitors and IL-36 blockers have yielded mixed results. A recent phase 3 trial in Japan demonstrated the significant efficacy of apremilast in treating PPP, with a favorable safety profile, suggesting that apremilast may be a promising treatment option for PPP. Due to PPP's lower prevalence compared with psoriasis vulgaris, clinical trials remain limited. Further large-scale, controlled studies are needed to clarify the efficacy and long-term safety of these therapies in diverse populations. This review summarizes emerging evidence on IL-23 inhibitors and other treatments for PPP, detailing their mechanisms of action, clinical efficacy, safety profiles, current challenges, and future perspectives in optimizing therapy.

关键词： MHC class I   tapasin   TAPBPR   peptide editing   peptide selection   immunopeptidome  

摘要： Major Histocompatibility Complex class I (MHC-I) molecules bind and present peptides to cytotoxic T cells, protecting against pathogens and cancer. MHC-I is highly polymorphic and each allotype is promiscuous, and capable of binding a unique and diverse repertoire of peptide ligands. The peptide editing chaperone tapasin optimizes this allotype specific repertoire of peptides, resulting in the selection of high affinity peptides. MHC-I allotypes differ in the extent they engage tapasin. This suggests that tapasin-dependent MHC-I allotypes should present a less diverse repertoire that is enriched in higher-affinity peptides, and which are present in higher abundance, than tapasin independent MHC-I allotypes, which should present a broader repertoire containing peptides with a lower average affinity. Experimental verification of this hypothesis has been confounded by the different peptide binding specificities of MHC-I allotypes. Here, we independently investigated the peptide focusing function of tapasin by introducing a point mutation into a tapasin independent MHC-I allotype that dramatically increased its tapasin dependence without substantially altering its peptide binding specificity. This allowed us to demonstrate ligand focusing by tapasin at both the repertoire level in cellulo, and by using an in vitro system in which tapasin was artificially tethered to MHC-I, at the individual peptide level. We found that tapasin had a greater influence on tapasin dependent MHC-I molecules, and that tapasin modulated peptide selection according to peptide-MHC-I complex stability, disfavoring short-lived peptide-MHC-I complexes. Thus, tapasin dependent MHC-I molecules experience greater tapasin filtering, resulting in less diverse MHC-I immunopeptidomes that are enriched in high affinity peptide-MHC-I complexes.

关键词： SDC4   NF-kappa B   Target gene   Cancer cells  

摘要： Syndecan-4 (SDC4), a key member of the sulfated heparan sulfate proteoglycan (SDC) family, plays an important role in cell signaling. However, its function and regulatory mechanisms in tumors remain poorly understood. In this study, bioinformatic analysis revealed that SDC4 is significantly overexpressed in 16 types of tumors and positively correlated with poor prognosis in four types of these diseases. Knockdown of SDC4 inhibited tumor cell migration. Further analysis showed six transcription factors, including NF-kappa B, which potentially regulate SDC4 transcription. The UCSC Genome Browser database showed NF-kappa B binding peaks covered the SDC4 promoter in TNF alpha-stimulated tumor cells. ChIP-qPCR assay confirmed that TNF alpha treatment led to NF-kappa B binding at the SDC4 promoter, a genomic region also enriched for the active transcription mark H3K27Ac. qRT-PCR results demonstrated that TNF alpha treatment upregulated SDC4 in tumor cells. Immunofluorescence assay or qRT-PCR showed that the NF-kappa B inhibitor Bay11-7082 blocked TNF alpha-induced nuclear translocation of NF-kappa B, while both qRT-PCR and Western blot analyses showed Bay11-7082 could inhibit TNF alpha-induced upregulation of SDC4 at both mRNA and protein levels. Furthermore, SDC4 expression was positively correlated with NF-kappa B subunit RelA expression across 22 tumor types. In conclusion, this study identifies SDC4 as an oncogenic target gene of NF-kappa B, providing new insights for the development of anti-tumor therapies targeting the NF-kappa B pathway.

摘要： Chronic graft-versus-host disease (cGVHD) remains the leading cause of nonrelapse morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Effective therapeutic agents targeting dysregulated cytokines including interleukin-17 (IL-17) and colony-stimulating factor 1 (CSF-1) have been defined in preclinical models of cGVHD, and efficacy in subsequent clinical trials has led to their recent US Food and Drug Administration approval. Despite this, these agents are effective in only a subset of patients, expensive, difficult to access outside the United States, and used in a trial-and-error fashion. The ability to readily discern druggable, dysregulated immunity in these patients is desperately needed to facilitate the selection of appropriate treatment and to potentially identify high-risk individuals for preemptive therapy. We used single-cell sequencing-based approaches in our informative preclinical cGVHD models to "reverse engineer" temporal IL-17 and CSF-1 signatures in mouse blood that could be used to interrogate patients. We defined distinct, nonintuitive IL-17 and CSF-1 signatures in mouse blood monocytes that could be identified in relevant monocyte populations within 70% of patients at diagnosis of cGVHD and in half of patients at day +100 after HCT who subsequently developed cGVHD. These signatures can now be evaluated prospectively in clinical studies to help delineate potential responder and nonresponders to relevant therapeutics targeting these pathways.

关键词： 传染性法氏囊病毒   单克隆抗体   检测方法   双抗体夹心ELISA  

摘要： 旨在建立一种快速有效的检测鸡传染性法氏囊病病毒（IBDV）的方法，本研究以IBDV全病毒作为免疫原制备单克隆抗体，以获得的单抗6G3作为捕获抗体，单抗4C12作为检测抗体，建立检测IBDV的双抗体夹心ELISA方法。结果表明，该ELISA方法具有良好的特异性，与REV、AEV、ALV和EDSV均无交叉反应；能检测病毒的最小量为1.585×103ELD50；批间和批内重复性试验显示，该方法具有良好的重复性；通过该方法对49份临床样品进行检测，与商品化的IBDV抗原检测卡进行比较，符合率达94.18%。综上，本研究建立的双抗体夹心ELISA方法，具有良好的特异性、敏感性和重复性，可用于IBDV 的快速检测，为制备商品化的IBDV检测试剂盒奠定基础。

关键词： MHC-I   adaptive immune responses   immune evasion   MHC-I assembly   MHC-I transport   MHC-I expression  

摘要： Among various pathogens, viruses pose significant threats to the livestock and poultry industry, resulting in substantial annual costs due to production losses and vaccination. The MHC-I presentation pathway is a crucial surveillance mechanism for preventing viral infections. Consequently, many viruses have evolved sophisticated strategies to inhibit the presentation of viral peptides by MHC-I to CD8+ T-cells, thereby evading the immune system. Understanding the mechanisms that suppress the MHC-I pathway and identifying specific binding peptides are essential for comprehending viral immune evasion and developing effective animal vaccines. This review summarizes the viral strategies for evading immune recognition, including the inhibition of MHC-I molecules synthesis, degradation, transport, and assembly, which affect MHC-I surface expression during viral infections. We also present evidence that MHC-I surface expression is frequently lost during numerous viral infections in livestock and poultry and offer new insights into the underlying mechanisms through which viruses inactivate the MHC-I antigen presentation pathway. Collectively, these advanced findings on viral evasion from the MHC-I pathway could inform the development of more effectives strategies to restore immunological control over viral infections and improve vaccines for the livestock and poultry industry.