Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 treatment has yielded clinical benefits in several ...types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that exosomes derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T-cell activity and promoting tumor growth. The abundance of PD-L1 on exosomes represented the quantity of PD-L1 expression on cell surfaces. Exosomes containing PD-L1 inhibited interferon-gamma (IFN-γ) secretion by Jurkat T cells. IFN-γ secretion was restored by PD-L1 knockout or masking on the exosomes. Both forced expression of PD-L1 on cells without PD-L1 and treatment with exosomes containing PD-L1 enhanced tumor growth in vivo. PD-L1 was present on exosomes isolated from the plasma of patients with non-small cell lung cancer, and its abundance in exosomes was correlated with PD-L1 positivity in tumor tissues. Exosomes can impair immune functions by reducing cytokine production and inducing apoptosis in CD8
T cells. Our findings indicate that tumor-derived exosomes expressing PD-L1 may be an important mediator of tumor immune escape.
Summary Fibroblast growth factor receptor 2 is a member of receptor tyrosine kinase family, and fibroblast growth factor receptor 2 gene amplification or missense mutation has been observed in ...various human cancers, including gastric carcinoma. Recent studies have shown that anti– fibroblast growth factor receptor 2 agents inhibit tumor progression in various human cancers, such as endometrial carcinoma and gastric carcinoma, which remains one of the most frequent causes of cancer-related death worldwide. We considered that knowledge of the status of fibroblast growth factor receptor 2 gene amplification in gastric carcinoma might aid in targeted cancer therapy. In this study, fibroblast growth factor receptor 2 amplification status was evaluated by fluorescence in situ hybridization in 313 surgically resected gastric carcinoma tissues, and the results were validated by quantitative real-time polymerase chain reaction. In addition, potential associations between clinicopathologic parameters and the presence of fibroblast growth factor receptor 2 amplification were investigated, and survival analysis was performed. Of the 313 cases, 14 (4.5%) showed fibroblast growth factor receptor 2 amplification by fluorescence in situ hybridization. Fibroblast growth factor receptor 2 amplification was found to be associated with a higher pT stage ( P = .023), higher pN stage ( P = .038), and distant metastasis ( P = .009) and to be significantly associated with lower cancer-specific survival by univariate analysis ( P = .012). Gastric carcinoma with fibroblast growth factor receptor 2 amplification was found to be associated with advanced disease and a poor prognosis. We believe that the determination of fibroblast growth factor receptor 2 amplification status could allow the identification of a subset of cancers sensitive to targeted fibroblast growth factor receptor 2 inhibitor–based therapy.
Efficient delivery of tumor antigens and immunostimulatory adjuvants into lymph nodes is crucial for the maturation and activation of antigen-presenting cells (APCs), which subsequently induce ...adaptive antitumor immunity. A dissolving microneedle (MN) has been considered as an attractive method for transcutaneous immunization due to its superior ability to deliver vaccines through the stratum corneum in a minimally invasive manner. However, because dissolving MNs are mostly prepared using water-soluble sugars or polymers for their rapid dissolution in intradermal fluid after administration, they are often difficult to formulate with poorly water-soluble vaccine components. Here, we develop amphiphilic triblock copolymer-based dissolving MNs in situ that generate nanomicelles (NMCs) upon their dissolution after cutaneous application, which facilitate the efficient encapsulation of poorly water-soluble Toll-like receptor 7/8 agonist (R848) and the delivery of hydrophilic antigens. The sizes of NMCs range from 30 to 40 nm, which is suitable for the efficient delivery of R848 and antigens to lymph nodes and promotion of cellular uptake by APCs, minimizing systemic exposure of the R848. Application of MNs containing tumor model antigen (OVA) and R848 to the skin of EG7-OVA tumor-bearing mice induced a significant level of antigen-specific humoral and cellular immunity, resulting in significant antitumor activity.
Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation, aberrant differentiation of keratinocytes, and dysregulated immune responses. WW domain-containing ...oxidoreductase (WWOX) is a non-classical tumor suppressor gene that regulates multiple cellular processes, including proliferation, apoptosis, and migration. This study aimed to explore the possible role of WWOX in the pathogenesis of psoriasis. Immunohistochemical analysis showed that the expression of WWOX was increased in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model. Immortalized human epidermal keratinocytes were transduced with a recombinant adenovirus expressing microRNA specific for WWOX to downregulate its expression. Inflammatory responses were detected using Western blotting, real-time quantitative reverse transcription polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay. In human epidermal keratinocytes, WWOX knockdown reduced nuclear factor-kappa B signaling and levels of proinflammatory cytokines induced by polyinosinic: polycytidylic acid (poly(I:C) in vitro. Furthermore, calcium chelator and protein kinase C (PKC) inhibitors significantly reduced poly(I:C)-induced inflammatory reactions. WWOX plays a role in the inflammatory reaction of epidermal keratinocytes by regulating calcium and PKC signaling. Targeting WWOX could be a novel therapeutic approach for psoriasis in the future.
Background
There is lack of data on effect modification by age on the association between body mass index (BMI) or waist circumference (WC) and cardiovascular diseases (CVDs). We aimed to investigate ...the impact of BMI and WC on incident CVDs in individuals aged 40 and 66 years.
Methods
Overall, 2 430 510 participants who underwent a national health screening for transitional ages provided by the Korean National Health Insurance Service between 2009 and 2012 were included. The adjusted hazard ratios and 95% confidence intervals for myocardial infarction (MI), ischaemic stroke and CVDs as a composite outcome of MI and ischaemic stroke were calculated using multivariable Cox proportional hazard regression analysis.
Results
During a mean follow‐up of 7.7 years, 24 884 MI and 29 415 ischaemic stroke events occurred. Among participants aged 40 years, there was a J‐shaped association of BMI with incident CVDs, MI and ischaemic stroke with nadir at BMI 18.5–22.9 kg/m2 (P for trend < 0.001 for all). Among those aged 66 years, there were significant U‐shaped associations of BMI with CVDs and MI with nadir at a BMI of 23.0–24.9 kg/m2 (P for trend 0.013 and 0.017, respectively). WC was linearly associated with all study outcomes in both age groups (P for trend < 0.001). The impact of general and abdominal obesity on both study outcomes was more prominent in those aged 40 years than in those aged 66 years (P for interaction < 0.001).
Conclusions
To prevent cardiovascular risk, weight loss intervention should be cautiously implemented and individualized according to age. The maintenance of muscle mass may be essential in managing weight loss particularly in older population.
The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum ...disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.
Key message
CRISPR/Cas9-based multiplexed editing of SlHyPRP1 resulted in precise deletions of its functional motif(s), thereby resulting in salt stress-tolerant events in cultivated tomato.
Crop ...genetic improvement to address environmental stresses for sustainable food production has been in high demand, especially given the current situation of global climate changes and reduction of the global food production rate/population rate. Recently, the emerging clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)-based targeted mutagenesis has provided a revolutionary approach to crop improvement. The major application of CRISPR/Cas in plant genome editing has been the generation of indel mutations via error-prone nonhomologous end joining (NHEJ) repair of DNA DSBs. In this study, we examined the power of the CRISPR/Cas9-based novel approach in the precise manipulation of protein domains of tomato hybrid proline-rich protein 1 (HyPRP1), which is a negative regulator of salt stress responses. We revealed that the precise elimination of SlHyPRP1 negative-response domain(s) led to high salinity tolerance at the germination and vegetative stages in our experimental conditions. CRISPR/Cas9-based domain editing may be an efficient tool to engineer multidomain proteins of important food crops to cope with global climate changes for sustainable agriculture and future food security.
Myeloid-derived suppressor cells (MDSCs) are heterogenous populations of immature myeloid progenitor cells with immunoregulatory function. MDSCs play critical roles in controlling the processes of ...autoimmunity but their roles in rheumatoid arthritis (RA) are controversial. The present study was undertaken to investigate whether MDSCs have therapeutic impact in mice with collagen-induced arthritis (CIA), an animal model of RA. We also examined the mechanisms underlying the anti-arthritic effect of MDSCs. In vitro treatment with MDSCs repressed IL-17 but increased FOXP3 in CD4+ T cells in mice. In vivo infusion of MDSCs markedly ameliorated inflammatory arthritis. Th17 cells and Th1 cells were decreased while Tregs were increased in the spleens of MDSCs-treated mice. MDSCs profoundly inhibited T cell proliferation. Addition of anti-IL-10 almost completely blocked the anti-proliferative effects of MDSCs on T cells. Anti-IL-10 blocked the expansion of Tregs by MDSCs. However, infusion of MDSCs from IL-10 KO mice failed to suppress inflammatory arthritis. MDSCs could reciprocally regulate Th17/Treg cells and suppress CIA via IL-10, suggesting that MDSCs might be a promising therapeutic strategy for T cell mediated autoimmune diseases including RA.
Glioblastoma (GBM), the most severe and common brain tumor in adults, is characterized by multiple somatic mutations and aberrant activation of inflammatory responses. Immune cell infiltration and ...subsequent inflammation cause tumor growth and resistance to therapy. Somatic loss-of-function mutations in the gene encoding tumor suppressor protein p53 (TP53) are frequently observed in various cancers. However, numerous studies suggest that TP53 regulates malignant phenotypes by gain-of-function (GOF) mutations. Here we demonstrate that a TP53 GOF mutation promotes inflammation in GBM. Ectopic expression of a TP53 GOF mutant induced transcriptomic changes, which resulted in enrichment of gene signatures related to inflammation and chemotaxis. Bioinformatics analyses revealed that a gene signature, upregulated by the TP53 GOF mutation, is associated with progression and shorter overall survival in GBM. We also observed significant correlations between the TP53 GOF mutation signature and inflammation in the clinical database of GBM and other cancers. The TP53 GOF mutant showed upregulated C-C motif chemokine ligand 2 (CCL2) and tumor necrosis factor alpha (TNFA) expression via nuclear factor kappa B (NFκB) signaling, consequently increasing microglia and monocyte-derived immune cell infiltration. Additionally, TP53 GOF mutation and CCL2 and TNFA expression correlated positively with tumor-associated immunity in patients with GBM. Taken together, our findings suggest that the TP53 GOF mutation plays a crucial role in inflammatory responses, thereby deteriorating prognostic outcomes in patients with GBM.
Background The incidence of food allergies has increased dramatically during the last decade. Recently, probiotics have been studied for the prevention and treatment of allergic disease. Objective We ...examined whether Bifidobacterium longum KACC 91563 and Enterococcus faecalis KACC 91532 have the capacity to suppress food allergies. Methods B longum KACC 91563 and E faecalis KACC 91532 were administered to BALB/c wild-type mice, in which food allergy was induced by using ovalbumin and alum. Food allergy symptoms and various immune responses were assessed. Results B longum KACC 91563, but not E faecalis KACC 91532, alleviated food allergy symptoms. Extracellular vesicles of B longum KACC 91563 bound specifically to mast cells and induced apoptosis without affecting T-cell immune responses. Furthermore, injection of family 5 extracellular solute-binding protein, a main component of extracellular vesicles, into mice markedly reduced the occurrence of diarrhea in a mouse food allergy model. Conclusion B longum KACC 91563 induces apoptosis of mast cells specifically and alleviates food allergy symptoms. Accordingly, B longum KACC 91563 and family 5 extracellular solute-binding protein exhibit potential as therapeutic approaches for food allergies.
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