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Journal For Immunotherapy of Cancer Jun 2024Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and...
BACKGROUND
Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential.
METHODS
Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors.
RESULTS
EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice.
CONCLUSIONS
MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.
Topics: Animals; Mice; Humans; Matrix Metalloproteinase 9; Macrophages; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Receptors, Cell Surface; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Receptors, Antigen, T-Cell; Tumor Microenvironment; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female; T-Lymphocytes; Immunotherapy, Adoptive
PubMed: 38886114
DOI: 10.1136/jitc-2023-008375 -
PLoS Genetics Jun 2024PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy...
PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy of immunotherapy, highlighting its important role in the regulation of tumor immunity. Nevertheless, our understanding of the intricate interplay between PLK1 and the tumor microenvironment (TME) remains incomplete. Here, using genetically engineered mouse model and single-cell RNA-seq analysis, we report that PLK1 promotes an immunosuppressive TME in LUAD, characterized with enhanced M2 polarization of tumor associated macrophages (TAM) and dampened antigen presentation process. Mechanistically, elevated PLK1 coincides with increased secretion of CXCL2 cytokine, which promotes M2 polarization of TAM and diminishes expression of class II major histocompatibility complex (MHC-II) in professional antigen-presenting cells. Furthermore, PLK1 negatively regulates MHC-II expression in cancer cells, which has been shown to be associated with compromised tumor immunity and unfavorable patient outcomes. Taken together, our results reveal PLK1 as a novel modulator of TME in LUAD and provide possible therapeutic interventions.
Topics: Protein Serine-Threonine Kinases; Animals; Polo-Like Kinase 1; Tumor Microenvironment; Mice; Proto-Oncogene Proteins; Cell Cycle Proteins; Single-Cell Analysis; Humans; Lung Neoplasms; Adenocarcinoma of Lung; Histocompatibility Antigens Class II; Tumor-Associated Macrophages; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Chemokine CXCL2; Antigen Presentation
PubMed: 38885192
DOI: 10.1371/journal.pgen.1011309 -
Frontiers in Oncology 2024Somatic mutations in have been identified across various tumors, playing pivotal roles in tumorigenesis, tumor progression, and unfavorable prognoses. Despite its... (Review)
Review
Somatic mutations in have been identified across various tumors, playing pivotal roles in tumorigenesis, tumor progression, and unfavorable prognoses. Despite its established notoriety as an oncogenic driver, there is a growing interest in exploring the involvement of MYCN in human development. While variants have traditionally been associated with Feingold syndrome type 1, recent discoveries highlight gain-of-function variants, specifically p.(Thr58Met) and p.(Pro60Leu), as the cause for megalencephaly-polydactyly syndrome. The elucidation of cellular and murine analytical data from both loss-of-function (Feingold syndrome model) and gain-of-function models (megalencephaly-polydactyly syndrome model) is significantly contributing to a comprehensive understanding of the physiological role of MYCN in human development and pathogenesis. This review discusses the MYCN's functional implications for human development by reviewing the clinical characteristics of these distinct syndromes, Feingold syndrome, and megalencephaly-polydactyly syndrome, providing valuable insights into the understanding of pathophysiological backgrounds of other syndromes associated with the MYCN pathway and the overall comprehension of MYCN's role in human development.
PubMed: 38884091
DOI: 10.3389/fonc.2024.1417607 -
Journal of Thoracic Disease May 2024With the need for "actionable histology" in the current era of targeted cancer treatment, and the increasing practice of upfront thoracoscopy (without a prior diagnostic...
BACKGROUND
With the need for "actionable histology" in the current era of targeted cancer treatment, and the increasing practice of upfront thoracoscopy (without a prior diagnostic thoracentesis) or a "biopsy first" approach in suspected malignant pleural effusions (MPEs), we sought to prospectively evaluate the diagnostic accuracy, including full molecular profiling of cancer, and safety of medical thoracoscopy (MT) at a tertiary referral hospital.
METHODS
Patients with MT performed for an undiagnosed pleural effusion between January 2020 and December 2022 were included in this observational cohort study. All procedures were performed with a semirigid thoracoscope under conscious sedation. Clinical outcomes and adverse events were recorded prospectively.
RESULTS
We evaluated 141 patients, with a mean age of 67±12 years. Talc poudrage was performed in 67 (47.5%) patients with a median of 2 [interquartile range (IQR), 1-4] hospitalisation days after MT. Upfront thoracoscopy was performed in approximately half (55.3%) of patients. The overall diagnostic accuracy of MT was 95.7% in our cohort. A final diagnosis of cancer was made in 116 (82.3%) patients, with lung (67.2%) and breast cancer (8.6%) the most common. The diagnostic sensitivity of MT for malignancy was 94.8%, and molecular profiling of relevant cancer types for oncogenic mutations was achieved in all patients with malignancy seen on histopathology. The most common non-malignant diagnosis was tuberculous pleuritis in 14 patients (9.9%). Major complications occurred in 3 (2.1%) patients. Two patients had re-expansion pulmonary edema that resolved with low flow oxygen supplementation in the general ward, and one patient required intensive care unit admission for cardiac tamponade from a malignant pericardial effusion. There were no cases of mortality, bleeding complications or persistent air leaks.
CONCLUSIONS
MT is a well-tolerated and effective option for the evaluation of undiagnosed pleural effusions. With expanding utility and expertise with MT and other pleural interventions, the challenge for respiratory physicians is integrating these into expeditious diagnostic and effective therapeutic pathways, individualised to patients' needs.
PubMed: 38883638
DOI: 10.21037/jtd-24-219 -
Biochemia Medica Jun 2024Hairy cell leukemia (HCL) represents 2% of all leukemia cases, with men aged above 55 years being the most affected. The most common symptoms of this type of leukemia... (Review)
Review
Hairy cell leukemia (HCL) represents 2% of all leukemia cases, with men aged above 55 years being the most affected. The most common symptoms of this type of leukemia include splenomegaly, monocytopenia, and neutropenia. In the basic blood count examination, leukopenia with monocytopenia and granulocytopenia, as well as aplastic anemia and/or thrombocytopenia occur. The mutation of β-rapidly accelerated fibrosarcoma () proto-oncogene, which can be found in nearly 100% of patients, is an important feature of HCL. Immunophenotypic analysis of the HCL cells reveals high expression of B-lineage antigens, including CD19, CD20, and CD22. Additionally, CD11c, CD25, CD103, and CD123 belong to specific markers of HCL. Lactate dehydrogenase activity and β-2-microglobulin concentration are also important in the patient's assessment. The differential diagnosis between HCL, hairy cell leukemia variant (HCL-V) and splenic marginal zone lymphoma (SMZL) is of first importance. Currently, the main treatment for HCL involves the use of purine analogues, excluding pregnant women, individuals with severe infections, and those with relapsing HCL.
Topics: Humans; Leukemia, Hairy Cell; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Diagnosis, Differential; Male; Mutation
PubMed: 38882583
DOI: 10.11613/BM.2024.020502 -
Translational Cancer Research May 2024Osteosarcoma (OS) is an exceptionally aggressive bone neoplasm that predominantly impacts the paediatric and adolescent population, exhibiting unfavourable prognosis....
BACKGROUND
Osteosarcoma (OS) is an exceptionally aggressive bone neoplasm that predominantly impacts the paediatric and adolescent population, exhibiting unfavourable prognosis. The importance of RNA binding motif protein 14 () in the aetiology of OS is not well understood, despite its established involvement in several other types of cancer.
METHODS
In this study, we conducted an analysis of the expression profiles of in cancer tissues and cell lines. To achieve this, we will utilised data obtained from various databases including The Cancer Genome Atlas Program (TCGA) project, The Genotype-Tissue Expression (GTEx) Project, Gene Expression Omnibus (GEO) database, and cancer cell line encyclopedia (CCLE) data. Furthermore, this study also aims to examine the effects of on the proliferation, migration, and invasive properties of OS cells using cell functional gain and loss studies. In this study, we carried out an in-depth investigation to explore possible molecular pathways that underlie the regulation of the malignant phenotype found in OS by . This investigation involved integrating data from overexpression, knockdown RNA-seq experiments, and an array comprising 6,096 perturbed genes obtained from the Genetic Perturbation Similarity Analysis Database (GPSAdb). This research offers an opportunity to build a robust conceptual framework for the potential advancement of novel therapeutic approaches that are especially aimed at attacking OS.
RESULTS
plays an active role in OS by significantly contributing to the enhancement of cellular proliferation, migration, and invasion. At the molecular level, it is probable that exerts control over the malignant characteristics of OS through its modulation of the Hippo signalling system.
CONCLUSIONS
The above-mentioned findings underscore the significant importance of as an intriguing target for therapy for the mitigation and management of OS. This particular protein holds an excellent opportunity for the development of novel and efficacious therapeutic approaches that possess the potential to yield favorable results for patients affected with OS.
PubMed: 38881928
DOI: 10.21037/tcr-23-2070 -
Frontiers in Immunology 2024Mast cells are critically involved in IgE-mediated diseases, e.g., allergies and asthma. Human mast cells are heterogeneous, and mast cells from different anatomical...
BACKGROUND
Mast cells are critically involved in IgE-mediated diseases, e.g., allergies and asthma. Human mast cells are heterogeneous, and mast cells from different anatomical sites have been shown to respond differently to certain stimuli and drugs. The origin of the mast cells is therefore of importance when setting up a model system, and human lung mast cells are highly relevant cells to study in the context of asthma. We therefore set out to optimize a protocol of IgE-mediated activation of human lung mast cells.
METHODS
Human lung mast cells were extracted from lung tissue obtained from patients undergoing pulmonary resection by enzyme digestion and mechanical disruption followed by CD117 magnetic-activated cell sorting (MACS) enrichment. Different culturing media and conditions for the IgE-mediated degranulation were tested to obtain an optimized method.
RESULTS
IgE crosslinking of human lung mast cells cultured in serum-free media gave a stronger response compared to cells cultured with 10% serum. The addition of stem cell factor (SCF) did not enhance the degranulation. However, when the cells were put in fresh serum-free media 30 minutes prior to the addition of anti-IgE antibodies, the cells responded more vigorously. Maximum degranulation was reached 10 minutes after the addition of anti-IgE. Both CD63 and CD164 were identified as stable markers for the detection of degranulated mast cells over time, while the staining with anti-CD107a and avidin started to decline 10 minutes after activation. The levels of CD203c and CD13 did not change in activated cells and therefore cannot be used as degranulation markers of human lung mast cells.
CONCLUSIONS
For an optimal degranulation response, human lung mast cells should be cultured and activated in serum-free media. With this method, a very strong and consistent degranulation response with a low donor-to-donor variation is obtained. Therefore, this model is useful for further investigations of IgE-mediated mast cell activation and exploring drugs that target human lung mast cells, for instance, in the context of asthma.
Topics: Humans; Mast Cells; Cell Degranulation; Immunoglobulin E; Lung; Cells, Cultured; Proto-Oncogene Proteins c-kit; Culture Media, Serum-Free; Antibodies, Anti-Idiotypic
PubMed: 38881896
DOI: 10.3389/fimmu.2024.1393802 -
Cancer Control : Journal of the Moffitt... 2024Cervical cancer is the fourth most common cancer in women. Advanced stage and metastatic disease are often associated with poor clinical outcomes. This substantiates the... (Review)
Review
Cervical cancer is the fourth most common cancer in women. Advanced stage and metastatic disease are often associated with poor clinical outcomes. This substantiates the absolute necessity for high-throughput diagnostic and treatment platforms that are patient and tumour specific. Cervical cancer treatment constitutes multimodal intervention. Systemic treatments such as chemotherapy and/or focal radiotherapy are typically applied as neoadjuvant and/or adjuvant strategies. Cisplatin constitutes an integral part of standard cervical cancer treatment approaches. However, despite initial patient response, or delayed/acquired treatment resistance is often reported, and toxicity is of concern. Chemotherapy resistance is associated with major alterations in genomic, metabolomic, epigenetic and proteomic landscapes. This results in imbalanced homeostasis associated with pro-oncogenic and proliferative survival, anti-apoptotic benefits, and enhanced DNA damage repair processes. Although significant developments in cancer diagnoses and treatment have been made over the last two decades, drug resistance remains a major obstacle to overcome.
Topics: Humans; Uterine Cervical Neoplasms; Female; Drug Resistance, Neoplasm; Mutation; Antineoplastic Agents
PubMed: 38881031
DOI: 10.1177/10732748241261539 -
Zhongguo Fei Ai Za Zhi = Chinese... May 2024Lung cancer is the most common malignant disease and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung... (Review)
Review
Lung cancer is the most common malignant disease and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers, and the probability of NSCLC gene mutations is high, with a wide variety of types. With the development of next-generation sequencing (NGS) detection technology, more and more patients with rare fusion gene mutations are detected. Neuregulin 1 (NRG1) gene is a rare oncogenic driver that can lead to activation of human epidermal growth factor receptor 3 (Her3/ErbB3) mediated pathway, resulting in tumor formation. In this article, we reported a case of mixed NSCLC with CRISPLD2-NRG1 fusion detected by RNA-based NGS, who responsed to Afatinib well after 1 month of treatment, and magnetic resonance imaging (MRI) showed shrinkage of intracranial lesions. Meanwhile, we also compiled previously reported NSCLC patients with NRG1 rare gene fusion mutation, in order to provide effective references for clinical diagnosis and treatment. .
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Neuregulin-1; Afatinib; Oncogene Proteins, Fusion; Middle Aged; Male; Cell Adhesion Molecules; Female
PubMed: 38880928
DOI: 10.3779/j.issn.1009-3419.2024.102.19 -
Molecular Cancer Jun 2024The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in...
The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1/CAMSAP3 cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1/CAMSAP3 cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients.
Topics: Humans; Female; Endometrial Neoplasms; Prognosis; Biomarkers, Tumor; Proteomics; Gene Expression Regulation, Neoplastic; Neoplasm Staging; Tumor Microenvironment; Gene Expression Profiling; Middle Aged; Transcriptome; Multiomics; HSP90 Heat-Shock Proteins
PubMed: 38880903
DOI: 10.1186/s12943-024-02039-2