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International Journal of Medical... 2024Metastasis and immunosuppression result in unfavorable prognosis in bladder cancer (BLCA). FGL1 and FGL2 are two members of the fibrinogen-related proteins family, but...
Metastasis and immunosuppression result in unfavorable prognosis in bladder cancer (BLCA). FGL1 and FGL2 are two members of the fibrinogen-related proteins family, but their potential effects on BLCA remain elusive. The expression profile of FGL1 and FGL2 in BLCA was analyzed in multiple databases. Furthermore, the expression of FGL2 was validated in BLCA tissues. The predictive capability of FGL2 was evaluated by Kaplan-Meier analysis, univariate analysis, and multivariate Cox regression. A nomogram model was constructed based on FGL2 expression and clinicopathological parameters for clinical practice. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analyses (GSEA) were performed to investigate enrichment in the biological processes. In addition, the correlation between FGL2 and immunological characteristics in the BLCA tumor microenvironment (TME), including tumor-infiltrating immune cells (TICs), cancer-immunity cycles, immune checkpoint molecules (ICPs), immunophenoscores (IPS), and response to anti-PD-L1 immunotherapy was further analyzed. FGL2 was found to be downregulated in BLCA due to hypermethylation of the FGL2 promoter region, which was associated with an unfavorable prognosis. Moreover, BLCA patients with high FGL2 expression exhibited better response to immunotherapy. Our research revealed that FGL2 was downregulated in BLCA and was negatively correlated with DNA methylation. High FGL2 expression was confirmed as an independent risk for prognosis. Moreover, FGL2 is a promising indicator for the response to immunotherapy in patients with BLCA.
Topics: Humans; Urinary Bladder Neoplasms; Biomarkers, Tumor; Prognosis; Immunotherapy; Tumor Microenvironment; Gene Expression Regulation, Neoplastic; Fibrinogen; Male; Female; Nomograms; DNA Methylation; Middle Aged; Aged; Kaplan-Meier Estimate
PubMed: 38903931
DOI: 10.7150/ijms.91874 -
International Journal of Medical... 2024PtdIns (3,4,5) P3-dependent Rac exchanger 1 (PREX1), also known as PREX1, a member of the Rac guanine nucleotide exchange factors (Rac-GEF) family. Studies have...
PtdIns (3,4,5) P3-dependent Rac exchanger 1 (PREX1), also known as PREX1, a member of the Rac guanine nucleotide exchange factors (Rac-GEF) family. Studies have suggested that PREX1 plays a role in mediating oncogenic pathway activation and controlling various biological mechanisms in different types of cancer, including liver hepatocellular carcinoma (LIHC). However, the function of PREX1 in the pathogenesis of LIHC and its potential role on immunological regulation is not clearly elucidated. The expression level and the clinical role of PREX1 in LIHC was analyzed based on database from the Cancer Genome Atlas (TCGA), TNM plotter and University of Alabama Cancer Database (UALCAN). We investigated the relationship between PREX1 and immunity in LIHC by TISIDB, CIBERSORT and single cell analysis. Immunotherapy responses were assessed by the immunophenoscores (IPS). Moreover, biological functional assays were performed to further investigate the roles of PREX1 in liver cancer cell lines. Higher expression of PREX1 in LIHC tissues than in normal liver tissues was found based on public datasets. Further analysis revealed that PREX1 was associated with worse clinical characteristics and dismal prognosis. Pathway enrichment analysis indicated that PREX1 participated in immune-related pathways. Through CIBERSORT and single cell analysis, we found a remarkable correlation between the expression of PREX1 and various immune cells, especially macrophages. In addition, high PREX1 expression was found to be associated with a stronger response to immunotherapy. Furthermore, assays indicated that depletion of PREX1 can suppress invasion and proliferation of LIHC cells. Elevated expression of PREX1 indicates poor prognosis, influences immune modulation and predicts sensitivity of immunosuppression therapy in LIHC. Our results suggested that PREX1 may be a prognostic biomarker and therapeutic target, offering new treatment options for LIHC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Prognosis; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Single-Cell Analysis; Gene Expression Profiling; Cell Line, Tumor; Guanine Nucleotide Exchange Factors; Male; Transcriptome; Phospholipid Transfer Proteins; Tumor Microenvironment; Female
PubMed: 38903921
DOI: 10.7150/ijms.94812 -
Frontiers in Immunology 2024Although the chronic lymphocytic leukemia (CLL) treatment landscape has changed dramatically, unmet clinical needs are emerging, as CLL in many patients does not... (Review)
Review
Although the chronic lymphocytic leukemia (CLL) treatment landscape has changed dramatically, unmet clinical needs are emerging, as CLL in many patients does not respond, becomes resistant to treatment, relapses during treatment, or transforms into Richter. In the majority of cases, transformation evolves the original leukemia clone into a diffuse large B-cell lymphoma (DLBCL). Richter transformation (RT) represents a dreadful clinical challenge with limited therapeutic opportunities and scarce preclinical tools. CLL cells are well known to highly depend on survival signals provided by the tumor microenvironment (TME). These signals enhance the frequency of immunosuppressive cells with protumor function, including regulatory CD4 T cells and tumor-associated macrophages. T cells, on the other hand, exhibit features of exhaustion and profound functional defects. Overall immune dysfunction and immunosuppression are common features of patients with CLL. The interaction between malignant cells and TME cells can occur during different phases of CLL development and transformation. A better understanding of CLL and RT biology and the availability of adequate mouse models that faithfully recapitulate the progression of CLL and RT within their microenvironments are " to develop successful therapeutic strategies. In this review, we describe the xenograft and genetic-engineered mouse models of CLL and RT, how they helped to elucidate the pathophysiology of the disease progression and transformation, and how they have been and might be instrumental in developing innovative therapeutic approaches to finally eradicate these malignancies.
Topics: Leukemia, Lymphocytic, Chronic, B-Cell; Animals; Tumor Microenvironment; Humans; Mice; Disease Models, Animal; Cell Transformation, Neoplastic; Lymphoma, Large B-Cell, Diffuse
PubMed: 38903501
DOI: 10.3389/fimmu.2024.1376660 -
Kidney International Reports Jun 2024Earlier reports suggest that patients after ABO-incompatible kidney transplantation (ABOi) are at enhanced risk of developing BK-virus (BKV, also known as BK...
INTRODUCTION
Earlier reports suggest that patients after ABO-incompatible kidney transplantation (ABOi) are at enhanced risk of developing BK-virus (BKV, also known as BK polyomavirus [BKPyV]) nephropathy (BKPyVAN). It remains elusive whether this is a result of more intense immunosuppression or an ABOi-associated "intrinsic attribute." To address this question, we measured Torque Teno virus (TTV) loads as a quantitative proxy for immunosuppressive depth in ABOi recipients and compared them to human leukocyte antigen-incompatible (HLAi, i.e. pretransplant donor-specific antibody-positive) and standard-risk transplant recipients.
METHODS
Our retrospective study screened 2256 consecutive kidney transplantations performed between 2007 and 2020 at the Medical University of Vienna. Out of 629 in-principle eligible transplantations, we were able to include 465 patients: 42 ABOi, 106 HLAi, and 317 control recipients. Longitudinal TTV- polymerase chain reaction (PCR) and BKV-PCR was carried out at predefined timepoints and ranged from pretransplant until month 24 posttransplantation. TTV loads and immunosuppression were evaluated in the context of BKV-associated complications.
RESULTS
ABOi recipients had a higher TTV load compared to HLAi and controls both at month 3 (median 1.5 × 10 vs. 2.4 × 10 vs. 9.1 × 10; = 0.010) and at month 6 (3.1 × 10 vs. 1.4 × 10 vs. 6.4 × 10; = 0.014) posttransplantation. Tacrolimus exposure was significantly higher in ABOi patients compared to HLAi and control patients (ABOi vs. HLAi: = 0.007; ABOi vs. controls: < 0.0001). Biopsy-proven BKPyVAN was more frequent in ABOi recipients when compared to HLAi and control recipients (11.9% vs. 2.8% vs. 4.1%; = 0.046).
CONCLUSION
Our data support the assumption that ABOi patients are indeed at higher risk to develop BKPyVAN. A higher TTV load and immunosuppressive burden suggest that intense immunosuppression, rather than an "intrinsic attribute" conferred by ABOi, may contribute to this finding.
PubMed: 38899213
DOI: 10.1016/j.ekir.2024.04.003 -
Journal of Translational Medicine Jun 2024The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and...
The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC.
Topics: Humans; Neutrophils; Animals; RNA-Binding Proteins; Cell Line, Tumor; Adaptor Proteins, Signal Transducing; Tumor Microenvironment; Female; B7-H1 Antigen; Stomach Neoplasms; Male; Mice; Drug Resistance, Neoplasm; Cell Movement; Immune Tolerance; Immunosuppression Therapy; Gene Expression Regulation, Neoplastic; Neoplasm Invasiveness; Mice, Nude; Immunotherapy; Middle Aged
PubMed: 38898490
DOI: 10.1186/s12967-024-05389-z -
Cell Death & Disease Jun 2024The interaction between glioblastoma cells and glioblastoma-associated macrophages (GAMs) influences the immunosuppressive tumor microenvironment, leading to ineffective...
The interaction between glioblastoma cells and glioblastoma-associated macrophages (GAMs) influences the immunosuppressive tumor microenvironment, leading to ineffective immunotherapies. We hypothesized that disrupting the communication between tumors and macrophages would enhance the efficacy of immunotherapies. Transcriptomic analysis of recurrent glioblastoma specimens indicated an enhanced neuroinflammatory pathway, with CXCL12 emerging as the top-ranked gene in secretory molecules. Single-cell transcriptome profiling of naïve glioblastoma specimens revealed CXCL12 expression in tumor and myeloid clusters. An analysis of public glioblastoma datasets has confirmed the association of CXCL12 with disease and PD-L1 expression. In vitro studies have demonstrated that exogenous CXCL12 induces pro-tumorigenic characteristics in macrophage-like cells and upregulated PD-L1 expression through NF-κB signaling. We identified CXCR7, an atypical receptor for CXCL12 predominantly present in tumor cells, as a negative regulator of CXCL12 expression by interfering with extracellular signal-regulated kinase activation. CXCR7 knockdown in a glioblastoma mouse model resulted in worse survival outcomes, increased PD-L1 expression in GAMs, and reduced CD8 T-cell infiltration compared with the control group. Ex vivo T-cell experiments demonstrated enhanced cytotoxicity against tumor cells with a selective CXCR7 agonist, VUF11207, reversing GAM-induced immunosuppression in a glioblastoma cell-macrophage-T-cell co-culture system. Notably, VUF11207 prolonged survival and potentiated the anti-tumor effect of the anti-PD-L1 antibody in glioblastoma-bearing mice. This effect was mitigated by an anti-CD8β antibody, indicating the synergistic effect of VUF11207. In conclusion, CXCL12 conferred immunosuppression mediated by pro-tumorigenic and PD-L1-expressing GAMs in glioblastoma. Targeted activation of glioblastoma-derived CXCR7 inhibits CXCL12, thereby eliciting anti-tumor immunity and enhancing the efficacy of anti-PD-L1 antibodies.
Topics: Glioblastoma; Humans; Animals; Receptors, CXCR; Chemokine CXCL12; Mice; B7-H1 Antigen; Cell Line, Tumor; Tumor Microenvironment; Brain Neoplasms; Signal Transduction
PubMed: 38898023
DOI: 10.1038/s41419-024-06784-6 -
Clinical Case Reports Jun 2024Anthracosis causes chronic lung inflammation and immunodeficiency, which are associated with parasitic conditions like lophomonas. Healthcare providers must consider...
KEY CLINICAL MESSAGE
Anthracosis causes chronic lung inflammation and immunodeficiency, which are associated with parasitic conditions like lophomonas. Healthcare providers must consider both anthracosis and pulmonary lophomoniasis when evaluating patients with respiratory symptoms, as early detection and treatment can lead to better outcomes for affected individuals. Proper diagnosis and management of these conditions can help prevent complications and improve overall lung health.
ABSTRACT
Anthracosis is a chronic pulmonary disease characterized by black pigmentation of the bronchial mucosa due to carbon accumulation in the lungs. This condition can result in immunosuppression and make patients more susceptible to parasitic diseases. A 77-year-old patient was admitted with fever, dyspnea, and cough with whitish-yellow sputum that began 2 months ago. Symptoms worsened with partial response to outpatient treatment. Bronchoscopy was requested due to abnormal lab tests and CT scan findings. Bronchoscopy sample revealed anthracosis and microscopic analysis of BAL detected live oval flagellated lophomonas protozoa. Treatment consisted of bronchodilators, corticosteroids, and antibiotic therapy. Anthracosis is linked to parasite diseases, such as lophomonas; thus, concurrent pulmonary lophomoniasis should be considered when anthracosis is identified. Healthcare providers must be vigilant in diagnosing and treating both anthracosis and pulmonary lophomoniasis, as the presence of one may indicate the possibility of the other.
PubMed: 38895051
DOI: 10.1002/ccr3.9085 -
Cancers May 2024Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curative for HCC tumors within the... (Review)
Review
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curative for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists and/or to downstage patients who are beyond the Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine kinase inhibitors (TKIs) can be used as a systemic bridging therapy to LT in patients with contraindications for locoregional liver-directed therapies. Immune checkpoint inhibitor (ICI) treatment can be utilized either as a monotherapy or as a combination therapy with bevacizumab or TKIs prior to LT. Acute rejection after liver transplantation is a concern in the context of ICI treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.
PubMed: 38893200
DOI: 10.3390/cancers16112081 -
Cancers May 2024In breast cancer, epithelial-mesenchymal transition (EMT) is positively associated with programmed death ligand 1 (PD-L1) expression and immune escape, and TWIST1...
In breast cancer, epithelial-mesenchymal transition (EMT) is positively associated with programmed death ligand 1 (PD-L1) expression and immune escape, and TWIST1 silences ERα expression and induces EMT and cancer metastasis. However, how TWIST1 regulates PD-L1 and immune evasion is unknown. This study analyzed TWIST1 and PD-L1 expression in breast cancers, investigated the mechanism for TWIST1 to regulate PD-L1 transcription, and assessed the effects of TWIST1 and PD-L1 in cancer cells on cytotoxic CD8+ T cells. Interestingly, TWIST1 expression is correlated with high-level PD-L1 expression in ERα-negative breast cancer cells. The overexpression and knockdown of TWIST1 robustly upregulate and downregulate PD-L1 expression, respectively. TWIST1 binds to the PD-L1 promoter and recruits the TIP60 acetyltransferase complex in a BRD8-dependent manner to transcriptionally activate PD-L1 expression, which significantly accelerates the exhaustion and death of the cytotoxic CD8+ T cells. Accordingly, knockdown of TWIST1 or BRD8 or inhibition of PD-L1 significantly enhances the tumor antigen-specific CD8+ T cells to suppress the growth of breast cancer cells. These results demonstrate that TWIST1 directly induces PD-L1 expression in ERα-negative breast cancer cells to promote immune evasion. Targeting TWIST1, BRD8, and/or PD-L1 in ERα-negative breast cancer cells with TWIST1 expression may sensitize CD8+ T-cell-mediated immunotherapy.
PubMed: 38893094
DOI: 10.3390/cancers16111973 -
International Journal of Molecular... Jun 2024Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is... (Review)
Review
Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies.
Topics: Humans; Breast Neoplasms; Cyclooxygenase 2; Female; Nitric Oxide Synthase Type II; Disease Progression; Tumor Microenvironment; Animals; Nitric Oxide; Gene Expression Regulation, Neoplastic; Reactive Nitrogen Species
PubMed: 38892290
DOI: 10.3390/ijms25116103