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Objective: To evaluate the immunosuppressive effect on human phagocytes and antibacterial activity of dihydromorin and norartocarpetin isolated from Artocarpus heterophyllus heartwoods. Methods: Dihydromorin and norartocarpetin were isolated from Artocarpus heterophyllus heartwoods. A modified Boyden chamber was used to determine the chemotactic activity of human phagocyte. The respiratory burst was evaluated by chemiluminescence assay. Myeloperoxidase (MPO) activity was quantified using a colorimetric assay. The broth microdilution method was performed to assess their antibacterial activity. Results: Dihydromorin exhibited potent inhibitory effect on the chemotactic activity of polymorphonuclear neutrophils (PMNs) with an IC50 value of 5.03 μg/mL. Dihydromorin also inhibited reactive oxygen species production of whole blood cells, PMNs, and monocytes with IC50 values of 7.88, 7.59 and 7.24 μg/mL, respectively. Interestingly, dihydromorin also strongly inhibited the MPO activity of PMNs with an IC50 value of 5.24 μg/mL, which was lower than indomethacin (24.6 μg/mL). Molecular docking of dihydromorin and crystal structure of MPO showed that dihydromorin had close interaction with key amino acid residues such as Arg239 and Gln91. Antibacterial activity assay showed that only dihydromorin had a strong effect against Streptococcus pyogenes with MIC and MBC values of 15.62 and 31.25 μg/mL, respectively. Conclusions: The results suggest that dihydromorin could be developed as an anti-inflammatory and antibacterial agent.

Azathioprine (Azp) is the principal immunosuppressive drug used in organ transplantation autoimmune diseases by improving therapeutic management and suppressing the immune system. Any discrepancy of Azp in human blood may lead to some serious side effects that obligate its quantitative estimation. In this work, the molybdenum disulfide (MoS2) nanosheets modified with poly(5-carboxyindole) (CPIn) is reported for quantitative estimation of Azp. The synthesis of MoS2 nanosheets is reported through single-step one-pot hydrothermal reaction and exfoliation of sheets is obtained in an aqueous dispersion of 5-carboxyindole (5CIn) through probe ultra-sonication. The nanosheets are further utilized as a template for the growth of the poly(5-carboxyindole) to obtain CPIn stabilized MoS2 nanosheets (MoS2-CPIn). The synthesis of MoS2-CPIn nanohybrid is further validated via different characterization techniques including FTIR, XRD, SEM, TEM, and XPS. MoS2-CPIn with magnificent electrocatalytic property is further exploited for the electroanalytical sensing of Azp via Differential Pulse Voltammetry (DPV) in phosphate buffer solution at biological pH (pH = 7.4) as well as human blood serum at room temperature. The proposed sensor shows a linear dependence of current with Azp concentration. The developed sensor demonstrates an extensively wide linear range of 3.49–284.44 µM possessing a low limit of detection of 74.65 nM (S/N = 3). The developed sensor shows excellent stability, sensitivity, and good selectivity in physiological pH. The achieved analytical parameters of the proposed sensor for easy quantification of Azp are found to be comparable or better than the previously reported Azp sensors and it is proved to be an excellent contestant for the trace level estimation of Azp in human blood serum.

Colorectal cancer (CRC) represents one of the most common causes of death among cancers worldwide. Its incidence has been increasing among the young population. Many risk factors contribute to the development and progression of CRC and about 70% of them are sporadic. The CRC microenvironment is highly heterogeneous and represents a very complex immunosuppressive platform. Many cytokines and their receptors are vital participants in this immunosuppressive microenvironment. Tumor necrosis factors (TNFs) and TNF receptor 2 (TNFR2) are critical players in the development of CRC. TNFR2 was observed to have increased the immunosuppressive activity of CRC cells via regulatory T cells (T regs) and myeloid-derived suppressor cells (MDSC) in the CRC microenvironment. However, the exact mechanism of TNFR2 in regulating the CRC prognosis remains elusive. Here, we discuss the role of TNFR2 in immune escape mechanism of CRC in the immunosuppressive cells, including Tregs and MDSCs, and the complex signaling pathways that facilitate the development of CRC. It is suggested that extensive studies on TNFR2 downstream signaling must be done, since TNFR2 has a high potential to be developed into a therapeutic agent and cancer biomarker in the future.

Psoriatic patients present an increased risk for developing lymphoma, particularly cutaneous T-cell lymphoma (CTCL). To what degree psoriasis itself through chronic immune stimulation, or the immunosuppressive medications used for its treatment or comorbidities (obesity, diabetes mellitus, etc), or lifestyle (smoking, alcohol, diet, etc) may play a role in the onset of MF is not yet clear. Psoriasis and Mycosis Fungoides (MF), the most common variant of CTCL, represent two distinct entities sharing common pathogenetic mechanisms and a wide spectrum of common clinical features associated with the abnormal activation of T-cells. The aim of this study is to explore the relationship between MF and psoriasis by presenting two cases with clinical and histopathologic features of both psoriasis and MF with a particular emphasis on the time of presentation of both disorders, the use of previous immunosuppressive drugs as well as the therapeutic management of patients. Biopsy of the cutaneous lesions before the introduction of biologics should be incorporated in clinical practice. Biopsy of the cutaneous lesion should also be performed in the case of appearance of psoriasiform lesions during biologic treatment for autoimmune disorders because this may represent an indolent form of MF. Psoriatic patients with poor or no-response to treatment should be examined thoroughly for MF using immunochemistry and, if necessary, molecular biology techniques. In concomitant MF and psoriasis, combination treatment may be beneficial for both entities. Finally, a large multicentric registry of MF patients who were treated for benign dermatoses (i.e. eczema, psoriasis) with classic immunosuppressive drugs and/or biologics is needed to collect data and further clarify the enigmatic relationship between psoriasis, MF and immunosuppressive treatment.

Endometriosis is an inflammatory disease that presents with ectopic endometriotic lesions. Reduced immunosurveillance of these lesions has been proposed to be playing a role in the pathology of endometriosis. Mesenchymal stromal cells (MSC) are found in ectopic lesions and may decrease immunosurveillance. In the present study, we examined if MSC contribute to reduced immunosurveillance through their immunosuppressive effects on natural killer (NK) cells. Stromal cells from endometriotic ovarian cysts (ESCcyst) and eutopic endometrium (ESCendo) of women with endometriosis and their conditioned medium were used in co-cultures with allogeneic peripheral blood NK cells. Following culture, NK cells were examined phenotypically for their expression of activating, inhibitory, maturation, and adhesion receptors and co-receptors, as well as the degranulation (CD107a) marker and the immunostimulatory (interferon-γ) and immunosuppressive (transforming growth factor beta 1 and interleukin-10) cytokines. Moreover, NK cell cytotoxicity was examined using chromium 51 release killing assays. There were no differences between ESCcyst and ESCendo regarding their effects on NK cell cytotoxicity in both conditioned medium and direct co-culture experiments. Additionally, there were no differences between ESCcyst and ESCendo regarding their impact on NK cells’ phenotype and degranulation in both conditioned medium and direct co-culture experiments. Although there were no differences found for DNAX accessory molecule-1 (DNAM-1) and NKp44, we found that the expression of the NK cell ligand CD155 that binds DNAM-1 and proliferating cell nuclear antigen (PCNA) that binds NKp44 was significantly less on ESCcyst than on ESCendo. These findings were not supported by the results that the expression of the known and unknown ligands on ESCcyst for DNAM-1 and NKp44 using chimeric proteins was not significantly different compared to ESCendo. In conclusion, the results suggest that ectopic MSC may not contribute to reduced immunosurveillance in endometriosis through their inhibitory effects on NK cells. This suggests that NK cell inhibition in the pelvic cavity of women with endometriosis develops due to other factors.

Plasma cell neoplasms (PCNs) in post solid organ transplant is a rare occurrence. To date, there is no standardized protocol for treatment. Management is further complicated in World Trade Center (WTC) survivors who present with post- solid organ transplant PCNs. This poses a challenge in management in order to reconcile the use of necessary immunosuppressive therapy (IST) with chemotherapy or immunotherapy and the potential toxic side effects. We report a case of a 59 year old WTC survivor with a history of orthotopic liver transplant (2015) for NASH cirrhosis on IST who was diagnosed with IgG lambda multiple myeloma (MM) in June 2019. The induction regimen of cyclophosphamide, bortezomib and dexamethasone (CyBorD) was initiated. Labs and clinical evaluation showed a very good partial response (VGPR). In January 2020, the patient presented with transaminitis and hyperbilirubinemia. CT abdomen and pelvis indicated multiple low-attenuation hepatic lesions. Ultrasound-guided core liver biopsy revealed malignant plasma cell neoplasm. The patient underwent endoscopic retrograde cholaniopancreatography (ERCP) with intraductal biliary stent placement in an attempt to alleviate the extrinsic obstruction from the hepatic lesions. The procedure was unsuccessful and the patient subsequently developed overt jaundice and progressive ascites. He was started on modified dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP). Unfortunately, liver failure progressed with enlarging liver lesions, at which point the patient elected hospice and died. This case highlights the fulminant course of PCNs post solid organ transplant. This is an area of unmet need for standardized treatment regimen in these poor prognostic cases. In addition, the case illustrates the complexity involved with management of such patients. A multidisciplinary medical team is needed to manage such patients’ complicated disease course.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction. Herein, an inflamed joint‐targeting delivery platform is developed based on platelet‐derived extracellular vesicles (PEVs) that are naturally occurring nanoparticles released by platelets, loaded with berberine (BBR) for suppressing the progress of RA. It is found that PEVs could selectively target the inflamed arthritis site in RA mice. In addition, BBR‐loaded PEVs exert anti‐inflammatory effects by reshaping the inflammatory environment in affected joints. It is shown that intravenous injection of BBR‐loaded PEVs into RA mice can effectively reduce joint swelling and bone erosion and restore mobility compared with free drug therapy. This strategy can effectively enhance the efficacy of RA treatment with limited side effects.

Osteosarcoma (OS) is the most common primary bone malignancy and has a high propensity for local invasion and metastasis. The tumour microenvironment of OS is infiltrated by a large number of immune cells, which play a crucial role in its progression and prognosis. Mast cells are important innate immune cells in the tumour stroma and exhibit different phenotypes in diverse tumour microenvironments. However, the underlying mechanisms of mast cell accumulation and the phenotypic characteristics of mast cells in OS remain poorly understood. In this article, we found for the first time that mast cell accumulation in osteosarcoma tissue was modulated by the CXCL6-CXCR2 axis and that the number of infiltrating mast cells was significantly greater in tumour tissues than in adjacent nontumour tissues. These tumour-infiltrating mast cells express high levels of the immunosuppressive molecule PD-L2, and survival analyses revealed that patients in the PD-L2 + high-expression group had a worse prognosis. In vitro , mast cells were induced to express PD-L2 in a time- and dose-dependent manner using OS tissue culture supernatants to mimic the tumour microenvironment. Mechanistic studies revealed that tumour cell-derived G-CSF significantly induced mast cell PD-L2 expression by activating STAT3. Importantly, mast cells overexpressing PD-L2 inhibit tumour-specific CD8 + T-cell proliferation and tumour-killing cytokine secretion, which is reversed by blocking PD-L2 on mast cells. Therefore, our findings provide new insight into the immunosuppressive and tumorigenic roles of mast cells, as well as a novel mechanism by which PD-L2-expressing mast cells mediate immune tolerance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Background: Natural Killer (NK) cells are vital components of the innate immune system, crucial for combating infections and tumor growth, making them pivotal in cancer prognosis and immunotherapy. We sought to understand the diverse characteristics of NK cells within lung adenocarcinoma (LUAD) by conducting single-cell RNA sequencing analyses., Methods: Using the scRNA-seq dataset for multiple primary lung cancers (MPLCs), we examined two major NK cell groups, NK1 and NK2, comparing the expression profiles of 422 differentially expressed NK signature genes. We identified eight genes (SPON2, PLEKHG3, CAMK2N1, RAB27B, CTBP2, EFHD2, GOLM1, and PLOD1) that distinguish NK1 from NK2 cells. A prognostic signature, the NK gene signature (NKGS) score, was established through LASSO Cox regression. High NKGS scores were linked to poorer overall survival in TCGA-LUAD patients and consistently validated in other datasets (GSE31210 and GSE14814)., Results: Functional analysis revealed an enrichment of genes related to the TGF-β signaling pathway in the high NKGS score group. Moreover, a high NKGS score correlated with an immunosuppressive tumor microenvironment (TME) driven by immune evasion mechanisms. We also observed reduced T-cell receptor (TCR) repertoire diversity in the high-risk NKGS group, indicating a negative association between inflammation and risk score., Conclusion: This study introduced the innovative NKGS score, differentiating NK1 from NK2 cells. High NKGS scores were associated with the TGF-β pathway and provided insights into LUAD prognosis and immune activities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Tumor cells have evolved to express immunosuppressive molecules allowing their evasion from the host’s immune system. These molecules include programmed death ligands 1 and 2 (PD-L1 and PD-L2). Cancer cells can also produce acetylcholine (ACh), which plays a role in tumor development. Moreover, tumor innervation can stimulate vascularization leading to tumor growth and metastasis. The effects of atropine and muscarinic receptor 3 (M3R) blocker, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), on cancer growth and spread were evaluated in vitro using murine colon cancer cell line, CT-26, and in vivo in an orthotopic mouse model of colorectal cancer. In the in vitro model, atropine and 4-DAMP significantly inhibited CT-26 cell proliferation in a dose dependent manner and induced apoptosis. Atropine attenuated immunosuppressive markers and M3R via inhibition of EGFR/AKT/ERK signaling pathways. However, 4-DAMP showed no effect on the expression of PD-L1, PD-L2, and choline acetyltransferase (ChAT) on CT-26 cells but attenuated M3R by suppressing the phosphorylation of AKT and ERK. Blocking of M3R in vivo decreased tumor growth and expression of immunosuppressive, cholinergic, and angiogenic markers through inhibition of AKT and ERK, leading to an improved immune response against cancer. The expression of immunosuppressive and cholinergic markers may hold potential in determining prognosis and treatment regimens for colorectal cancer patients. This study’s results demonstrate that blocking M3R has pronounced antitumor effects via several mechanisms, including inhibition of immunosuppressive molecules, enhancement of antitumor immune response, and suppression of tumor angiogenesis via suppression of the AKT/ERK signaling pathway. These findings suggest a crosstalk between the cholinergic and immune systems during cancer development. In addition, the cholinergic system influences cancer evasion from the host’s immunity.

Tumor protein D52-like 2 (TPD52L2) belongs to the members of the TPD52 family. TPD52L2 was reported to regulate proliferation and apoptosis in cancer cells. However, its role in lung adenocarcinoma (LUAD) was uncertain. We evaluated the expression, methylation, copy number alteration, and prognostic significance of TPD52L2 using RNA-seq data from The Cancer Genome Atlas (TCGA). Enrichment analysis of TPD52L2 was conducted using the R package "clusterProfiler." We further assessed the association between TPD52L2 and immune cell infiltration level, immunosuppressive genes, and tumor mutational burden (TMB). The difference of gene mutant frequency in high- and low-TPD52L2 groups was also analyzed. The results showed that TPD52L2 was over-expressed and predicted worse survival status in LUAD. We also found that TPD52L2 expression was positively associated with the infiltration levels of immunosuppressive cells, such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and negatively correlated with immune killer cells, such as CD8+ T and NK cells in pan-cancer, including LUAD. In addition, TPD52L2 expression was associated with immunosuppressive genes and TMB. High expression of TPD52L2 was with more mutant frequency of TP53. In summary, our results show that TPD52L2 is an oncogene and a potential prognostic biomarker in LUAD. High TPD52L2 expression is a possible indicator of immune infiltration and associated with tumor immunosuppressive status in LUAD. [ABSTRACT FROM AUTHOR]

Gliomas are a type of malignant central nervous system tumor with poor prognosis. Molecular biomarkers of gliomas can predict glioma patient's clinical outcome, but their limitations are also emerging. C-X-C motif chemokine ligand family plays a critical role in shaping tumor immune landscape and modulating tumor progression, but its role in gliomas is elusive. In this work, samples of TCGA were treated as the training cohort, and as for validation cohort, two CGGA datasets, four datasets from GEO database, and our own clinical samples were enrolled. Consensus clustering analysis was first introduced to classify samples based on CXCL expression profile, and the support vector machine was applied to construct the cluster model in validation cohort based on training cohort. Next, the elastic net analysis was applied to calculate the risk score of each sample based on CXCL expression. High-risk samples associated with more malignant clinical features, worse survival outcome, and more complicated immune landscape than low-risk samples. Besides, higher immune checkpoint gene expression was also noticed in high-risk samples, suggesting CXCL may participate in tumor evasion from immune surveillance. Notably, high-risk samples also manifested higher chemotherapy resistance than low-risk samples. Therefore, we predicted potential compounds that target high-risk samples. Two novel drugs, LCL-161 and ADZ5582, were firstly identified as gliomas' potential compounds, and five compounds from PubChem database were filtered out. Taken together, we constructed a prognostic model based on CXCL expression, and predicted that CXCL may affect tumor progression by modulating tumor immune landscape and tumor immune escape. Novel potential compounds were also proposed, which may improve malignant glioma prognosis. [ABSTRACT FROM AUTHOR]

Background: Recently, mesenchymal stem cells therapy has been performed in dogs, although the outcome is not always favorable. Objectives: To investigate the therapeutic efficacy of mesenchymal stem cells (MSCs) using dog leukocyte antigen (DLA) matching between the donor and recipient in vitro. Methods: Canine adipose-derived MSCs (cA-MSCs) isolated from the subcutaneous tissue of Dog 1 underwent characterization. For major DLA genotyping (DQA1, DQB1, and DRB1), peripheral blood mononuclear cells (PBMCs) from two dogs (Dogs 1 and 2) were analyzed by direct sequencing of polymerase chain reaction (PCR) products. The cA-MSCs were co-cultured at a 1:10 ratio with activated PBMCs (DLA matching or mismatching) for 3 days and analyzed for immunosuppressive (IDO, PTGS2, and PTGES), inflammatory (IL6 and IL10), and apoptotic genes (CASP8, BAX, TP53, and BCL2) by quantitative real-time reverse transcriptase-PCR. Results: cA-MSCs were expressed cell surface markers such as CD90+/44+/29+/45- and differentiated into osteocytes, chondrocytes, and adipocytes in vitro. According to the Immuno Polymorphism Database, DLA genotyping comparisons of Dogs 1 and 2 revealed complete differences in genes DQA1, DQB1, and DRB1. In the co-culturing of cA-MSCs and PBMCs, DLA mismatch between the two cell types induced a significant increase in the expression of immunosuppressive (IDO/PTGS2) and apoptotic (CASP8/BAX) genes. Conclusions: The administration of cA-MSCs matching the recipient DLA type can alleviate the need to regulate excessive immunosuppressive responses associated with genes, such as IDO and PTGES. Furthermore, easy and reliable DLA genotyping technology is required because of the high degree of genetic polymorphisms of DQA1, DQB1, and DRB1 and the low readability of DLA 88. [ABSTRACT FROM AUTHOR]

Fibroblast activation protein-α (FAP) is a type II integral serine protease that is specifically expressed by activated fibroblasts. Cancer-associated fibroblasts (CAFs) in the tumor stroma have an abundant and stable expression of FAP, which plays an important role in promoting tumor growth, invasion, metastasis, and immunosuppression. For example, in females with a high incidence of breast cancer, CAFs account for 50–70% of the cells in the tumor's microenvironment. CAF overexpression of FAP promotes tumor development and metastasis by influencing extracellular matrix remodeling, intracellular signaling, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. This review discusses the basic biological characteristics of FAP and its applications in the diagnosis and treatment of various cancers. We review the emerging basic and clinical research data regarding the use of nanomaterials that target FAP. [ABSTRACT FROM AUTHOR]

[Display omitted] • Chemokines orchestrate the immune architecture of tumors, influencing progression. • CCL18 is highly expressed in several tumors. • CCL18 promotes an immunosuppressive microenvironment and cancer cell invasion. • CCL18 has been correlated with poor prognosis in several types of cancer. • This chemokine is a promising biomarker/ therapeutic target in solid cancers. Chemokines are essential mediators of immune cell trafficking. In a tumor microenvironment context, chemotactic cytokines are known to regulate the migration, positioning and interaction of different cell subsets with both anti- and pro-tumor functions. Additionally, chemokines have critical roles regarding non-immune cells, highlighting their importance in tumor growth and progression. CCL18 is a primate-specific chemokine produced by macrophages and dendritic cells. This chemokine presents both constitutive and inducible expression. It is mainly associated with a tolerogenic response and involved in maintaining homeostasis of the immune system under physiological conditions. Recently, CCL18 has been noticed as an important component of the complex chemokine system involved in the biology of tumors. This chemokine induces T regulatory cell differentiation and recruitment to the tumor milieu, with subsequent induction of a pro-tumor (M2-like) macrophage phenotype. CCL18 is also directly involved in cancer cell-invasion, migration, epithelial-to-mesenchymal transition and angiogenesis stimulation, pinpointing an important role in the promotion of cancer progression. Interestingly, this chemokine is highly expressed in tumor tissues, particularly at the invasive front of more advanced stages (e.g. colorectal cancer), and high levels are detected in the serum of patients, correlating with poor prognosis. Despite the promising role of CCL18 as a biomarker and/or therapeutic target to hamper disease progression, its pleiotropic functions in a context of cancer are still poorly explored. The scarce knowledge concerning the receptors for this chemokine, together with the insufficient insight on the downstream signaling pathways, have impaired the selection of this molecule as an immediate target for translational research. In this Review, we will discuss recent findings concerning the role of CCL18 in cancer, integrate recently disclosed molecular mechanisms and compile data from current clinical studies. [ABSTRACT FROM AUTHOR]

Immunomodulatory agents are often used in the systemic treatment of non-infectious uveitis. These drugs consist of corticosteroids, conventional immunosuppressives, and biological agents. As it is known that they suppress the immune system, the most important concern associated with immunomodulatory therapy (IMT) is the increased risk of infection. The World Health Organization declared COVID-19 a pandemic on 11 March 2020. Although severe acute respiratory distress syndrome secondary to SARS-CoV-2 infection may develop in all people, patients who receive IMT may be at higher risk in terms of both the transmission of the infection and more severe disease course. Therefore, guidelines on the management of patients receiving IMT due to uveitis during the pandemic are needed. In this review, we examined the immunomodulatory drugs used in the treatment of uveitis in terms of infectious complications and the data of patients who received IMT during the COVID-19 pandemic and discussed recommendations for the use of these drugs. According to the latest information, patients who receive IMT may continue their treatment as long as there are no disruptions in regular complete blood count (especially white blood cell count >4,000/μL) and liver and kidney function tests. Patients diagnosed with COVID-19 should be managed with a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

Lymph node metastasis indicates a poor prognosis in colorectal cancer. To better understand the underlying mechanisms of lymph node metastasis, we analyzed transcriptome characteristics of the pre-metastatic lymph node, a putative microenvironment favorable for the seeding and proliferation of cancer cells. Thus, we tried to compare and elucidate the transcriptional and immune characteristics of sentinel lymph nodes (SNs) with matched non-sentinel lymph nodes (NSNs) in colorectal cancer patients. In this study, a total of 38 pairs of SNs and NSNs were collected, in which 26 pairs of non-metastatic lymph nodes were subjected to RNA-seq and bioinformatics analysis for the gene expression profiles. There were 16 differentially expressed genes between SNs and NSNs being identified, including 9 upregulated and 7 downregulated genes in SN. Gene Ontology (GO) classification analysis revealed that the differentially expressed genes were mainly involved in leukocyte differentiation, chemokine secretion, and immune system regulation. In the meantime, gene set enrichment analysis (GSEA) showed that immune-related signaling pathways, such as transforming growth factor beta (TGF-β) signaling and tumor necrosis factor alpha (TNF-α)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, were enriched in NSN, while cell proliferation–related signaling pathways were enriched in SN, including MYC signaling and G2M checkpoint signaling. We further identified SIGLEC15 as a top upregulated gene in SN. However, RNAscope assay showed that SIGLEC15 was not largely co-expressed with M2 macrophage marker CD163. We then selected eight pairs of lymph nodes for further cytological studies. Flow cytometry analysis revealed that Siglec-15 was expressed on all myeloid cell subsets. The relative expression of SEGLEC15 (SN/NSN) was correlated with the microsatellite instability (MSI) status in colorectal cancer patients. Further studies found that small interfering ribonucleic acid (siRNA)-mediated silencing of SLGLEC15 can enhance the anti-tumor function of T cells, as indicated by cytokine release analysis. In conclusion, we presented here a first report on the gene expression profiling of the pre-metastatic lymph node in colorectal cancer. The findings in this study suggest that SIGLEC15 plays an important role in SN immunosuppression. SEGLEC15 silencing could be a therapeutic strategy for restoring T cell function in tumor SNs.

Tumor protein D52-like 2 (TPD52L2) belongs to the members of the TPD52 family. TPD52L2 was reported to regulate proliferation and apoptosis in cancer cells. However, its role in lung adenocarcinoma (LUAD) was uncertain. We evaluated the expression, methylation, copy number alteration, and prognostic significance of TPD52L2 using RNA-seq data from The Cancer Genome Atlas (TCGA). Enrichment analysis of TPD52L2 was conducted using the R package “clusterProfiler.” We further assessed the association between TPD52L2 and immune cell infiltration level, immunosuppressive genes, and tumor mutational burden (TMB). The difference of gene mutant frequency in high- and low-TPD52L2 groups was also analyzed. The results showed that TPD52L2 was over-expressed and predicted worse survival status in LUAD. We also found that TPD52L2 expression was positively associated with the infiltration levels of immunosuppressive cells, such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and negatively correlated with immune killer cells, such as CD8+ T and NK cells in pan-cancer, including LUAD. In addition, TPD52L2 expression was associated with immunosuppressive genes and TMB. High expression of TPD52L2 was with more mutant frequency of TP53. In summary, our results show that TPD52L2 is an oncogene and a potential prognostic biomarker in LUAD. High TPD52L2 expression is a possible indicator of immune infiltration and associated with tumor immunosuppressive status in LUAD.

Gliomas are a type of malignant central nervous system tumor with poor prognosis. Molecular biomarkers of gliomas can predict glioma patient’s clinical outcome, but their limitations are also emerging. C-X-C motif chemokine ligand family plays a critical role in shaping tumor immune landscape and modulating tumor progression, but its role in gliomas is elusive. In this work, samples of TCGA were treated as the training cohort, and as for validation cohort, two CGGA datasets, four datasets from GEO database, and our own clinical samples were enrolled. Consensus clustering analysis was first introduced to classify samples based on CXCL expression profile, and the support vector machine was applied to construct the cluster model in validation cohort based on training cohort. Next, the elastic net analysis was applied to calculate the risk score of each sample based on CXCL expression. High-risk samples associated with more malignant clinical features, worse survival outcome, and more complicated immune landscape than low-risk samples. Besides, higher immune checkpoint gene expression was also noticed in high-risk samples, suggesting CXCL may participate in tumor evasion from immune surveillance. Notably, high-risk samples also manifested higher chemotherapy resistance than low-risk samples. Therefore, we predicted potential compounds that target high-risk samples. Two novel drugs, LCL-161 and ADZ5582, were firstly identified as gliomas’ potential compounds, and five compounds from PubChem database were filtered out. Taken together, we constructed a prognostic model based on CXCL expression, and predicted that CXCL may affect tumor progression by modulating tumor immune landscape and tumor immune escape. Novel potential compounds were also proposed, which may improve malignant glioma prognosis.

Fibroblast activation protein-α (FAP) is a type II integral serine protease that is specifically expressed by activated fibroblasts. Cancer-associated fibroblasts (CAFs) in the tumor stroma have an abundant and stable expression of FAP, which plays an important role in promoting tumor growth, invasion, metastasis, and immunosuppression. For example, in females with a high incidence of breast cancer, CAFs account for 50–70% of the cells in the tumor’s microenvironment. CAF overexpression of FAP promotes tumor development and metastasis by influencing extracellular matrix remodeling, intracellular signaling, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. This review discusses the basic biological characteristics of FAP and its applications in the diagnosis and treatment of various cancers. We review the emerging basic and clinical research data regarding the use of nanomaterials that target FAP.

Tripterygium wilfordii Hook. f. is a well-known traditional Chinese medicine used to treat autoimmune diseases. Sesquiterpene pyridine alkaloids (SPAs) are a major class of components found in this herb that have piqued the interest of researchers due to their complex and diverse structures as well as significant biological activities. In this study, ten new SPAs, wilfordatine A–J (1–10), were isolated from the roots of T. wilfordii, along with ten known analogues (11–20). Their structures were primarily elucidated by extensive 1D and 2D NMR spectroscopic analysis. To search for more immunosuppressive ingredients related to the clinical efficacy of T. wilfordii, the total alkaloids (TA) and compounds 4, 5, and 9–16 were tested for their inhibitory effects on nuclear factor-kappa B (NF-κB) pathway in Lipopolysaccharide (LPS) induced HEK293/NF-κB-Luc cells. Among them, TA, compounds 5, 11, and 16 showed potent immunosuppressive activity, with IC50 values of 7.25 μg/mL, 8.75 μM, 0.74 μM, and 15.66 μM, respectively, and no influence on the cell viability at a concentration of 100 μg/mL (TA) or 100 μM (5, 11, and 16). Accordingly, TA, 5, 11, and 16, especially 11, were identified as promising candidates for further investigation into their potential use as immunosuppressive agents.

Inducing antigen-specific tolerance is a promising treatment for preventing or reversing Type 1 diabetes (T1D). In contrast to a vaccine that induces immune responses against pathogens, a tolerogenic vaccine can suppress immunity against antigens causing diseases by administrating a mixture of self-antigens with an adjuvant that decreases the strength of antigen-specific response. Kynurenine (Kyn) is an endogenous substance that can inhibit the natural killer cell and T cell proliferation and promote the differentiation of naïve T cells into regulatory T cells (Tregs). In this study, we evaluated the efficacy of Kyn as a novel suppressive adjuvant. Kyn was co-immunized with GAD65 phage vaccine to induce Treg cells and tolerogenic responses for the prevention of T1D in NOD mouse model. Mice were subcutaneously immunized two times with 1011 Pfu (100μL,1012 Pfu/ml) GAD65 phage vaccine doses mixed with 200 μg of Kyn. Serum antibodies and cytokines were detected by ELISA and electrochemiluminescence, respectively. Flow cytometry assay was used to analyze DC and Treg. MTS was used for the analysis of spleen lymphocyte proliferation. RNA sequencing was used to investigate mRNA and miRNA expression profiles in spleen lymphocytes. Compared to GAD65 phage vaccine alone, co-immunization of Kyn and GAD65 phage vaccine resulted in the prevention of hyperglycemia in 60% of mice for at least one month. Further, Kyn enhances GAD65-specific Th2-mediated immune responses; regulates the Th1/Th2 imbalance and increases the secretion of Th2 cytokines and the number of CD4+CD25+Foxp3+T cells; suppresses DC maturation and GAD65-specific T lymphocyte proliferation. Moreover, we integrated Kyn related miRNA and mRNA expression profiles obtained from the spleen lymphocyte RNA-sequencing which was stimulated by Kyn in vitro. These data provide an important basis for understanding the mechanisms underlying Kyn as an immunosuppressive adjuvant which regulated the immune response. These findings suggest that Kyn can serve as an effective suppressive adjuvant candidate for Type 1 diabetes vaccines.

Background: An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC.Methods: We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan–Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. In vitro experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression.Results: Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-β, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through in vitro experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation.Conclusion: ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.

Abstract It is essential to differentiate intestinal tuberculosis from Crohn's disease because of the therapeutic implications of Crohn's disease, which can exacerbate the symptoms of tuberculosis.

Background: General role of cancer-associated fibroblast (CAF) and its infiltration characteristics in gastric cancer remains to be unknown.Methods: We estimate CAF infiltration in bulk tumor tissue with RNA-seq data and analyzed its relationship with gastric cancer subtype, survival and immune microenvironment.Results: We revealed CAF intend to have higher infiltration in diffuse, genomically stable, and advanced gastric cancer. CAF is associated with immunosuppressive microenvironment. Wide transcriptomics alterations occur in high CAF infiltrated gastric cancer, PI3K/AKT, TGFB and Hedgehog pathway are remarkable in this procedure. We utilized receptor tyrosine kinases and TGFB pathway ligands to construct risk score system that can predict survival.Conclusion: Thus, CAF is associated with aggressive phenotype of gastric cancer and risk score based on RTK and TGFB pathway ligands expression is a promising tool for assessment of gastric cancer survival. [ABSTRACT FROM AUTHOR]

Inducing antigen-specific tolerance is a promising treatment for preventing or reversing Type 1 diabetes (T1D). In contrast to a vaccine that induces immune responses against pathogens, a tolerogenic vaccine can suppress immunity against antigens causing diseases by administrating a mixture of self-antigens with an adjuvant that decreases the strength of antigen-specific response. Kynurenine (Kyn) is an endogenous substance that can inhibit the natural killer cell and T cell proliferation and promote the differentiation of naïve T cells into regulatory T cells (Tregs). In this study, we evaluated the efficacy of Kyn as a novel suppressive adjuvant. Kyn was co-immunized with GAD65 phage vaccine to induce Treg cells and tolerogenic responses for the prevention of T1D in NOD mouse model. Mice were subcutaneously immunized two times with 1011 Pfu (100μL,1012 Pfu/ml) GAD65 phage vaccine doses mixed with 200 μg of Kyn. Serum antibodies and cytokines were detected by ELISA and electrochemiluminescence, respectively. Flow cytometry assay was used to analyze DC and Treg. MTS was used for the analysis of spleen lymphocyte proliferation. RNA sequencing was used to investigate mRNA and miRNA expression profiles in spleen lymphocytes. Compared to GAD65 phage vaccine alone, co-immunization of Kyn and GAD65 phage vaccine resulted in the prevention of hyperglycemia in 60% of mice for at least one month. Further, Kyn enhances GAD65-specific Th2-mediated immune responses; regulates the Th1/Th2 imbalance and increases the secretion of Th2 cytokines and the number of CD4+CD25+Foxp3+T cells; suppresses DC maturation and GAD65-specific T lymphocyte proliferation. Moreover, we integrated Kyn related miRNA and mRNA expression profiles obtained from the spleen lymphocyte RNA-sequencing which was stimulated by Kyn in vitro. These data provide an important basis for understanding the mechanisms underlying Kyn as an immunosuppressive adjuvant which regulated the immune response. These findings suggest that Kyn can serve as an effective suppressive adjuvant candidate for Type 1 diabetes vaccines. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) with highly metastatic features generally does not respond to anti–programmed cell death 1 ligand 1 (PD-L1) therapy due to multiple immunosuppressive mechanisms to exclude and disable T cells. Here, we develop a polymer-based combinatory approach consisting of both immunogenic cell death (ICD)-inducing and CXCR4-inhibiting function to prime tumor microenvironment and improve anti-PD-L1 therapy in TNBC. Our findings revealed that the combination therapy was able to spur the T cell response in primary tumors by increasing the tumor immunogenicity to recruit T cells, removing the physiological barriers of intratumoral fibrosis and collagen to increase T cell infiltration, and reducing the immunosuppressive cells to revive T cells. Meanwhile, such approach efficiently inhibited the formation of pre-metastatic niche in abscopal lung. Because of the significant promotion of anti-tumor and anti-metastasis immunity, the non-responding TNBC gained robust responsiveness to anti-PD-L1 therapy which resulted in complete eradication of orthotopic tumors, inhibition of pulmonary metastasis, and durable memory effects against tumor recurrence. Our work provided a generalizable approach of simultaneous ICD induction and CXCR4 blockade to apply anti-PD-L1 therapy in TNBC. [Display omitted] [ABSTRACT FROM AUTHOR]

It is essential to differentiate intestinal tuberculosis from Crohn's disease because of the therapeutic implications of Crohn's disease, which can exacerbate the symptoms of tuberculosis. [ABSTRACT FROM AUTHOR]

Aims: There is currently no evidence-based guideline to show how to manage immunosuppressive treatment in patients with hidradenitis suppurativa (HS) during the Coronavirus disease-2019 (COVID-19) pandemic. Therefore, we updated our routine clinical protocol to 1) inform patients with ongoing treatment about the potential risks of their medications in the case of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, 2) discuss opt out of treatment temporarily, and 3) perform a closer follow-up on a monthly basis. The aim of this study was to evaluate the clinical outcomes in patients with HS, who suspended and continued immunosuppressive therapy following COVID-19 outbreak. Methods: This retrospective study included patients with HS, who had been receiving biologic/ immunosuppressive treatment when the COVID-19 pandemic was announced. Those who withdrew treatment for any reason or continued were analyzed. The primary endpoint was physician-diagnosed disease exacerbation. The secondary outcomes were changes in visual analogue scale (VAS) and COVID-19 diagnosis. Results: A total of 37 patients were included in the analysis. The majority of the patients were on adalimumab treatment (n=33). Fifteen (40.5%) patients withdrew the treatment for COVID-19 related concerns. During 83.2±0.6 days of follow-up following the withdrawal, all patients in this group had at least one exacerbation. Also, the mean VAS score increased from 5.7±0.56 to 8.6±0.57 (p=0.001). On the other hand, three patients (13.6%) who continued the treatment reported worsening in disease course, 12 patients (54.5%) remained stable and seven of them (31.9%) had clinical relief. We did not observe any confirmed SARS-CoV-2 infection in any of our 37 HS patients. Conclusions: The present study suggests that even a temporary withdrawal of biologic/ immunosuppressive treatments may have significant adverse consequences on disease course and quality of life in patients with HS. These individuals may safely continue the treatment provided that maximum measures are taken to avoid COVID-19 infection. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic skin disease that needs continuous medical care. During COVID‐19, delivering medical service was negatively affected. Aims: To describe the impact of COVID‐19 on psoriasis healthcare delivery, management, and practice. Methods: This observational cross‐sectional study was conducted on 197 dermatologists using a validated online questionnaire. The survey evaluated the effect of COVID‐19 on the decisions, prescription patterns, appointments rescheduling, and healthcare delivery for psoriasis patients by dermatologists. The questionnaire was developed and validated with a reliability score >0.7. Results: During the pandemic, most dermatologists delayed initiating biological/immunosuppressive therapy for psoriasis unless urgently needed by the patient. For patients already receiving biologics or immunosuppressive treatment, most dermatologists favored continuation of therapy. Almost half (44.2%) of participants do not perform SARS‐CoV‐2 PCR screening before initiating biologics/immunosuppressive therapy. Dermatologists also reported an increased prescription of topical medications (79.2%), natural sunlight (28.4%), acitretin (26.9%), and home UVB (21.3%). Opinions regarding the use of hydroxychloroquine for COVID‐19 treatment/prophylaxis for psoriasis patients were controversial. Intervals between face‐to‐face follow‐up visits were prolonged by 71.6% of dermatologists. More than half of participants reported that their patients discontinued treatment without medical consultation. More than three fourth of responders either agreed or strongly agreed that COVID‐19 negatively affected psoriasis patients. Conclusions: The COVID‐19 pandemic has a negative impact on psoriasis management and healthcare delivery. Dermatologists are cautious about using biologics and immunosuppressive drugs during the pandemic, making case‐by‐case decisions. Psoriasis patients need compliance monitoring, and psychological support during the pandemic, which can be facilitated by teledermatology. [ABSTRACT FROM AUTHOR]

Although various molecular subtypes of hepatocellular carcinoma (HCC) have been investigated, most of these studies identify HCC subtype based on genomic profiling. Few studies have investigated the classification based on immune signatures, and none have classified HCC based on Immune activation and immunosuppressive. We performed immune gene expression of tumor tissue in 374 HCC patients from The Cancer Genome Atlas (TCGA) database and used unsupervised consensus clustering to stratify tumors. We then used HCC patients from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) as replication datasets. Based on the expression of 782 immune-related genes, HCC was stratified into four distinct immune subtypes. Tumors in one cluster (high immune activation; high-IA) indicate a higher level of Immune activation, which was characterized by higher anti-tumor immunity, higher pro-tumor immune-suppressive cell types, higher fractions of CD8+ T cells and M0 Macrophages compared with other subtypes. The high-IA also presents higher cancer-related hallmark signatures, such as epithelial-mesenchymal transition (EMT), angiogenesis, and apoptosis. We also found subpopulations of regulatory and exhaustion T lymphocyte were characterized by an opposite trend in high-IA, though samples in high-IA response to immunotherapy with better survival. The comparison of the immune profile in tumor and normal tissue indicates the activation of immune responses which only occurred in high-IA patients, while we conducted comparison of cirrhosis and non-cirrhosis tumor immune signatures, immune response activation was almost occurred in high-IA, but some of immune responses occurred in low-IA (low immune activation). [ABSTRACT FROM AUTHOR]

[Display omitted] • Fifteen new sesquiterpenoid alkaloids were isolated from Celastrus monospermus. • Most of the isolates inhibited the proliferation of B lymphocyte (IC 50 = 1.4 ∼ 19.9 μM). • Compound 3 promoted the late-stage apoptosis of activated B lymphocyte. • Compounds 3, 16, and 20 inhibited osteoclast formation significantly at 1 μM. • The investigation enriched the structural diversity of sesquiterpenoid alkaloids. Phytochemical investigation of the stems of Celastrus monospermus Roxb enabled isolation and identification of fifteen new macrolide sesquiterpene pyridine alkaloids (1 – 15) along with five known analogues. Their structures were elucidated by comprehensive spectroscopic analysis (NMR, HRESIMS, IR, UV), chemical hydrolysis, and single crystal X-ray diffraction analysis. Bioassay of the abundant isolates revealed that seven compounds inhibited the proliferation of B lymphocytes with IC 50 values ranging between 1.4 and 19.9 μM. Among them, celasmondine C (3) could significantly promote the apoptosis of activated B lymphocyte, especially late-stage apoptosis. Besides, compounds 3 , 16 , and 20 exhibited potent suppression of osteoclast formation at a concentration of 1.0 μM. This investigation enriched the chemical diversity of macrolide sesquiterpene pyridine alkaloids, and supported evidence for the development of new immunosuppressive and anti-osteoclastogenesis agents. [ABSTRACT FROM AUTHOR]

A 28-year-old Indian female presented with sudden onset reduced vision and pain in the left eye following blunt trauma. There was chronic history of redness, tearing, and irritation in both the eyes. She was diagnosed with peripheral ulcerative keratitis and corneal perforation in the left eye. Her corneal perforation was repaired with direct closure. Diagnostic workup revealed limited granulomatosis polyangiitis. The patient was treated with topical and systemic steroids and immunosuppressant drugs (rituximab).

Abstract Background The etiology of idiopathic chronic hepatitis (ICH) in dogs is poorly understood, but evidence supports an immune‐mediated pathogenesis in some dogs. Objectives To describe a case series of dogs with presumed ICH treated with cyclosporine (CsA) with or without concurrent medications and to document the incidence of biochemical remission and factors associated with failure to attain remission. Animals Forty‐eight client‐owned dogs diagnosed with presumed ICH, treatment of which included CsA. Methods Two‐institution, retrospective case series of dogs between 2010 and 2017. All dogs were treated with CsA with or without concurrent medications for ≥2 weeks. Data were collected from medical records. Results Biochemical remission (

Serpiginous choroiditis (SC) is an asymmetrically bilateral inflammation of the choroid that leads to loss of choriocapillaris atrophy or loss of overlying retinal pigment epithelium. Over the last few decades, SC has passed through a long evolution of nomenclature, etiologies and morphological variations. Initially diagnosed in patients with tuberculosis and syphilis, SC was predominantly considered as autoimmune process. With the advancement of molecular diagnosis, a new aspect of infectious subtypes of SC has emerged out. The terminologies such as serpiginous-like choroiditis (SLC) and multifocal serpiginoid choroiditis are now used to denote the subtypes of SC which are associated with infectious etiologies especially tuberculosis. In a country endemic for tuberculosis such as India, it is very important to differentiate between classic SC and SLC before initiating aggressive immunomodulatory therapy. Also, management of paradoxical worsening of the clinical condition with antitubercular treatment is another challenge in SLC and ophthalmologists should be aware of such situations. With advent of newer imaging modalities, monitoring the patient with choroiditis and identification of complications such as choroidal neovascular membrane have become much easier. This article aims to review the existing literature on SC with a special emphasis on management of SC and SLC.

The growing insights in the complex interactions between metastatic cancer-cells and platelets have revealed that platelet tumor cell interactions in the blood stream are an important factor supporting tumor metastasis. An increased coagulability of platelets facilitates the vascular evasion and establishment of solid tumor metastasis. Furthermore, platelets can support an immunosuppressive tumor microenvironment or shield tumor cells directly from engagement of cytotoxic lymphocytes as e.g., natural killer (NK) cells. Platelets are both in the tumor microenvironment and systemically the quantitatively most important source of TGF-β, which is a key cytokine for immunosuppression in the tumor microenvironment. If similar platelet-tumor interactions are of physiological relevance in hematological malignancies remains less well-studied. This might be important, as T- and NK cell mediated graft vs. leukemia effects (GvL) are well-documented and malignant hematological cells have a high exposure to platelets compared to solid tumors. As NK cell-based immunotherapies gain increasing attention as a therapeutic option for patients suffering from hematological and other malignancies, we review the known interactions between platelets and NK cells in the solid tumor setting and discuss how these could also apply to hematological cancers. We furthermore explore the possible implications for NK cell therapy in patients with solid tumors and patients who depend on frequent platelet transfusions. As platelets have a protective and supportive effect on cancer cells, the impact of platelet transfusion on immunotherapy and the combination of immunotherapy with platelet inhibitors needs to be evaluated.

Endoplasmic reticulum (ER) stress has considerable impact on cell growth, proliferation, metastasis, invasion, angiogenesis and chemoradiotherapy resistance in various cancers. However, the effect of ER stress on the outcomes of glioma patients remains unclear. In this study, we established an ER stress risk model based on The Cancer Genome Atlas (TCGA) glioma data set to reflect immune characteristics and predict the prognosis of glioma patients. Survival analysis indicated that there were significant differences in the overall survival (OS) of glioma patients with different ER stress‐related risk scores. Moreover, the ER stress‐related risk signature, which was markedly associated with the clinicopathological properties of glioma patients, could serve as an independent prognostic indicator. Functional enrichment analysis revealed that the risk model correlated with immune and inflammation responses, as well as biosynthesis and degradation. In addition, the ER stress‐related risk model indicated an immunosuppressive microenvironment. In conclusion, we present an ER stress risk model that is an independent prognostic factor and indicates the general immune characteristics in the glioma microenvironment. [ABSTRACT FROM AUTHOR]

Aims: In the Danish population, we examined whether patients treated with thiopurines, methotrexate, systemic corticosteroids, anti‐tumour necrosis factor (TNF)‐α agents, anti‐interleukin therapeutic agents, selective immunosuppressive agents and cyclosporine/tacrolimus had an increased risk of hospitalization for COVID‐ 19, compared to the background population. Methods: A nationwide cohort study including all people alive in Denmark on 1 March 2020. Exposed patients constituted those exposed to thiopurines (n = 5484), methotrexate (n = 17 977), systemic corticosteroids (n = 55 868), anti‐TNF‐α agents (n = 17 857), anti‐interleukin therapeutic agents (n = 3744), selective immunosuppressive agents (n = 3026) and cyclosporine/tacrolimus (n = 1143) in a period of 12 months prior to 1 March 2020 (estimated time of outbreak in Denmark). We estimated the adjusted risk of hospitalization for COVID‐19 for patients treated with the above‐mentioned categories of medications, compared to the rest of the population. Results: The adjusted odds ratios of hospitalization in patients treated with corticosteroids and cyclosporine/tacrolimus were 1.64 (95% confidence interval [CI] 1.35 to 2.00) and 4.75 (95% CI 1.96 to 11.49), respectively. The risks of hospitalization in patients treated with thiopurines, methotrexate, and anti‐TNF‐α agents, were 1.93 (95% CI 0.91 to 4.08), 0.74 (95% CI 0.43 to 1.28), 1.00 (95% CI 0.52 to 1.94), respectively. The number of outcomes in patients treated with anti‐interleukin therapeutic agents and selective immunosuppressive agents was too small for analysis. Conclusion: Patients treated with systemic corticosteroids and cyclosporine/tacrolimus had a significantly increased risk of being hospitalized for COVID‐19. Our study does not uncover whether the increased risk is related to the drug itself, the underlying condition for which the patient is treated or other factors. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have become important seed cells in therapy because of their immunosuppressive function and anti-inflammatory effects. MSCs exert immunosuppressive effects through direct contact or paracrine action. The paracrine functions of MSCs are at least partially mediated by exosomes, which are membrane vesicles, carrying abundant proteins, nucleic acids and other active molecules. MSC-exos have heterogeneity. The exosomes from different donors, tissues generations of MSCs carry different bioactive molecules. These cargos are transferred to recipient cells by endocytosis or binding to proteins on the receptor surface to mediate intercellular communication between different cell types and affect the functions of the recipient cells. Exosomes play an important role in the regulation of the immune system. Exosomes derived from MSCs (MSC-exos) carry immunomodulatory effectors or transmit active signal molecules to regulate the biological activities of immune cells and thus mediating immune suppression, especially on macrophages and T cells. Mitochondria and autophagy-related pathways are also associated with MSC-exos immunosuppressive effects. [ABSTRACT FROM AUTHOR]

Most of the immunosuppressive drugs are used for the treatment of autoimmune disease, allergic diseases, and transplant rejection, but toxicity is the major obstacle for the potent drugs in the wide use of these immunosuppressive drugs. Daphnetin, a Chinese herbal product, has been reported that daphnetin possesses antimicrobial, anticoagulation, antimalarial, anticancer, and antioxidant activity. In a previous study, we found that daphnetin exhibited a potential immunosuppressive effect on LPS-induced B lymphocyte cells in vitro, therefore, in this research, we investigated the immunosuppressive effects of daphnetin in BALB/c mice use OVA as a prototype antigen. Sixty BALB/c mice were divided into six groups. The emulsion (100 μL containing 100 μg OVA) was injected subcutaneously with OVA + CFA into the shaved backs of the BALB/c mice on day 1, and a boosting injection was administered in OVA + IFA 2 weeks later. Beginning on the day of immunization, the immunized mice were administered intraperitoneally with daphnetin at a dose of 5, 10, and 20 mg/kg in saline solution for 28 consecutive days. We measured the effect of daphnetin on OVA-specific antibody, cytokine production, and Splenocyte proliferation in vivo. The results revealed that daphnetin significantly suppressed serum immunoglobulin G levels (IgG), and the OVA-specific IgG subclasses IgG1 and IgG2b, daphnetin was also significantly decreased the Th1 and Th2 cytokine productions, inhibited the splenocytes proliferation rate in vivo. It proved that daphnetin could suppress humoral response activity on OVA-sensitized mice, suggesting a potential role on daphnetin as a new immunosuppressive drug. [ABSTRACT FROM AUTHOR]

Feline Gastrointestinal Eosinophilic Sclerosing Fibroplasia (FGESF) is a rare clinical entity of unknown aetiology. The most defended hypothesis refers to a genetic alteration in the immune response regulation, which results in an exacerbated eosinophilic inflammation. The proposed treatment for FGESF includes immunosuppressive drugs and surgical resection of the lesion. A 2- and- a- half-year old neutered, male, Chartreux cat was diagnosed with FGESF with the presence of a mass in the first duodenal flexure, which was surgically removed and recurred 8 months post-surgery. After using an immunosuppressive treatment for one year, the macroscopic disappearance of the lesion and the complete remission of the clinical signs were achieved. To our knowledge, this is the first description of disappearance of a FGESF lesion located in the gastrointestinal tract after prolonged immunosuppressive treatment. This clinical report highlights the possibility to treat this new feline disease with the exclusive use of immunosuppressive drugs. [ABSTRACT FROM AUTHOR]

The growing insights in the complex interactions between metastatic cancer-cells and platelets have revealed that platelet tumor cell interactions in the blood stream are an important factor supporting tumor metastasis. An increased coagulability of platelets facilitates the vascular evasion and establishment of solid tumor metastasis. Furthermore, platelets can support an immunosuppressive tumor microenvironment or shield tumor cells directly from engagement of cytotoxic lymphocytes as e.g., natural killer (NK) cells. Platelets are both in the tumor microenvironment and systemically the quantitatively most important source of TGF-β, which is a key cytokine for immunosuppression in the tumor microenvironment. If similar platelet-tumor interactions are of physiological relevance in hematological malignancies remains less well-studied. This might be important, as T- and NK cell mediated graft vs. leukemia effects (GvL) are well-documented and malignant hematological cells have a high exposure to platelets compared to solid tumors. As NK cell-based immunotherapies gain increasing attention as a therapeutic option for patients suffering from hematological and other malignancies, we review the known interactions between platelets and NK cells in the solid tumor setting and discuss how these could also apply to hematological cancers. We furthermore explore the possible implications for NK cell therapy in patients with solid tumors and patients who depend on frequent platelet transfusions. As platelets have a protective and supportive effect on cancer cells, the impact of platelet transfusion on immunotherapy and the combination of immunotherapy with platelet inhibitors needs to be evaluated. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) and complex tumour immunosuppressive micro-environment posed austere challenges for combatting brain tumours such as the glioblastoma. In this study, we have developed a novel dual functional dendrimer drug delivery system (DDS) by the PAMAM and loaded with siLSINCT5 (NP- siRNA) for efficiently across the BBB to inhibit glioblastoma. To achieve the goal of BBB crossing, on the surface of NP-siRNA was decorated with the cell penetrating peptides tLyp-1 (tLypNP-siRNA). Moreover, to overcome the immunosuppressive microenvironment within the glioblastoma (GBM) tissues, a checkpoint inhibitor named as anti-NKG2A monoclonal antibody (aNKG2A), which was able of promoting anti-tumour immunity by unleashing both T and NK Cells, was further conjugated on the surface of siLSINCT5-loaded nanoparticles via the pH-sensitive linkage. Therefore, the developed dual functional and siLSINCT5-loaded dendrimer nanoparticles (tLyp/aNKNP-siRNA) was supposed to have the ability to efficiently cross the BBB and inhibit GBM by simultaneously inhibit the LSINCT5-activated signalling pathways and activate the anti-tumour immunity. The hypothesis was thoroughly confirmed by in vitro cellular and in vivo animal experiments, and provided a novel strategy for combating glioblastoma. [ABSTRACT FROM AUTHOR]

Paris criteria remain practical for retaining the diagnosis of overlap syndrome. While liver histology is mandatory, its absence should not be an obstacle to the diagnosis and delay the initiation of treatment in countries where biopsy not available. [ABSTRACT FROM AUTHOR]

Though rare due to measures and practices to control the risk, infections can occur in research and toxicology studies, especially in nonhuman primates (NHPs) exposed to xenobiotics, particularly immunomodulatory drugs. With such xenobiotics, immunocompromised or immunosuppressed animals will not be able to mount a protective response to infection by an opportunistic pathogen (bacteria, virus, parasite, or fungus) that might otherwise be nonpathogenic and remain clinically asymptomatic in immunocompetent animals. The respiratory tract is one of the most commonly affected systems in clinic, but also in toxicology studies. Pulmonary inflammation will be the main finding associated with opportunistic infections and may cause overt clinical disease with even early sacrifice or death, and may compromise or complicate the pathology evaluation. It is important to properly differentiate the various features of infection, to be aware of the range of possible opportunistic pathogens and how they may impact the interpretation of pathology findings. This review will present the most common bacterial, viral, parasitic, and fungal infections observed in the respiratory tract in NHPs during research and/or toxicology studies. [ABSTRACT FROM AUTHOR]

Highlights: Mechanisms underlying immunosuppressive tumor immune microenvironment (TIME) in ‘cold’ tumor are summarized. Recent nanotechnology-based strategies for ‘cold’ TIME firing up are emphasized. Challenges and perspectives of nanomedicines for ‘cold’ tumor treatment are proposed.Although current anticancer immunotherapies using immune checkpoint inhibitors (ICIs) have been reported with a high clinical success rate, numerous patients still bear ‘cold’ tumors with insufficient T cell infiltration and low immunogenicity, responding poorly to ICI therapy. Considering the advancements in precision medicine, in-depth mechanism studies on the tumor immune microenvironment (TIME) among cold tumors are required to improve the treatment for these patients. Nanomedicine has emerged as a promising drug delivery system in anticancer immunotherapy, activates immune function, modulates the TIME, and has been applied in combination with other anticancer therapeutic strategies. This review initially summarizes the mechanisms underlying immunosuppressive TIME in cold tumors and addresses the recent advancements in nanotechnology for cold TIME reversal-based therapies, as well as a brief talk about the feasibility of clinical translation. [ABSTRACT FROM AUTHOR]

Recognition of donor antigens by recipient T cells in secondary lymphoid organs initiates the adaptive inflammatory immune response leading to the rejection of allogeneic transplants. We present a unique case of a 38-year-old male with late allograft rejection due to immunosuppressive cytotoxic therapy. There is limited literature available as well as management. This case highlights the need for further investigative research of this entity and its pathogenesis. [ABSTRACT FROM AUTHOR]