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Journal For Immunotherapy of Cancer Jun 2024Immune checkpoint inhibitors (ICIs) can elicit anticancer immune responses, but predictive biomarkers are needed. We measured programmed death ligand 1 (PD-L1)...
Exploring the predictive potential of programmed death ligand 1 expression in healthy organs and lymph nodes as measured by F-BMS986-192 PET: pooled analysis of data from four solid tumor types.
INTRODUCTION
Immune checkpoint inhibitors (ICIs) can elicit anticancer immune responses, but predictive biomarkers are needed. We measured programmed death ligand 1 (PD-L1) expression in organs and lymph nodes using F-BMS-986192 positron emission tomography (PET)-imaging and looked for correlations with response and immune-related adverse events.
METHODS
Four F-BMS-986192 PET studies in patients with melanoma, lung, pancreatic and oral cancer, receiving ICI treatment, were combined. Imaging data (organ standardized uptake value (SUV), lymph node SUV) and clinical data (response to treatment and incidence of immune-related adverse events) were extracted.
RESULTS
Baseline PD-L1 uptake in the spleen was on average higher in non-responding patients than in responders (spleen SUV 16.1±4.4 vs 12.5±3.4, p=0.02). This effect was strongest in lung cancer, and not observed in oral cancer. In the oral cancer cohort, benign tumor-draining lymph nodes (TDLNs) had higher PD-L1 uptake (SUV 3.3 IQR 2.5-3.9) compared with non-TDLNs (SUV 1.8, IQR 1.4-2.8 p=0.04). Furthermore, in the same cohort non-responders showed an increase in PD-L1 uptake in benign TDLNs on-treatment with ICIs (+15%), while for responders the PD-L1 uptake decreased (-11%). PD-L1 uptake did not predict immune-related adverse events, though elevated thyroid uptake on-treatment correlated with pre-existing thyroid disease or toxicity.
CONCLUSION
PD-L1 PET uptake in the spleen is a potential negative predictor of response to ICIs. On-treatment with ICIs, PD-L1 uptake in benign TDLNs increases in non-responders, while it decreases in responders, potentially indicating a mechanism for resistance to ICIs in patients with oral cancer.
Topics: Humans; B7-H1 Antigen; Lymph Nodes; Positron-Emission Tomography; Male; Female; Neoplasms; Immune Checkpoint Inhibitors; Middle Aged; Aged
PubMed: 38886117
DOI: 10.1136/jitc-2024-008899 -
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 One 2024A retrospective study was conducted to explore the urinary expression of α 1-microglobulin (α1MG) and β2-microglobulin (β2MG) in patients with human immunodeficiency...
BACKGROUND
A retrospective study was conducted to explore the urinary expression of α 1-microglobulin (α1MG) and β2-microglobulin (β2MG) in patients with human immunodeficiency virus (HIV) infection, aiming to evaluate their predictive capability for renal injury.
METHOD
One hundred and five male HIV-infected patients treated with Tenofovir (TDF) regimen (TDF+3TC or the third drug TDF/FTC+) were selected between March 1, 2021, and March 1, 2022, in Wuhan Jinyintan Hospital. Three months after TDF treatment, the renal function injury was evaluated with the standard creatinine clearance rate. The urinary levels of α1MG and β2MG were compared between the initiation of TDF treatment and three months thereafter. Spearman correlation was utilized to analyze the correlation between the urinary expression of α1MG and β2MG and renal injury in HIV patients. The logistic regression was used to analyze the predictive value of urinary α1MG and β 2-microglobulin expression in renal injury.
RESULTS
Up to the first follow-up, 29 (27.6%) cases of the 105 male HIV patients had varying degrees of renal function injury, including 14 (13.3%) mild injury, 9 (8.6%) moderate injury, and 6 (5.7%) severe injury cases. Patients with severe renal injury had the highest levels of urinary α1MG and β2MG expression while those with mild injury demonstrated higher levels compared to the non-injury group (P < 0.05). Spearman correlation analysis indicated that urinary α1MG and β2MG were positively correlated with renal impairment in HIV patients (Rho = -0.568, and -0.732; P < 0.001). The ROC curve analysis demonstrated that the area under the curve (AUC) for urine α1MG and β2MG in predicting kidney damage among HIV patients were 0.928, 0.916, and 0.889, respectively. The sensitivity values were 96.55%, 82.76%, and 89.66% while the specificity values were 84.07%, 94.51%, and 89.29% for urine α1MG and β2MG, respectively.
CONCLUSION
The expression level of urinary α1MG and β2MG in HIV patients was significantly higher compared to normal people. Detection of these two indexes can enable early determination of renal injury and its severity in HIV patients.
Topics: Humans; Male; beta 2-Microglobulin; Alpha-Globulins; Tenofovir; HIV Infections; Biomarkers; Middle Aged; Adult; Retrospective Studies; Anti-HIV Agents; Acute Kidney Injury
PubMed: 38885284
DOI: 10.1371/journal.pone.0303442 -
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 -
ImmunoHorizons Jun 2024The individual HLA-related susceptibility to emerging viral diseases such as COVID-19 underscores the importance of understanding how HLA polymorphism influences peptide...
The individual HLA-related susceptibility to emerging viral diseases such as COVID-19 underscores the importance of understanding how HLA polymorphism influences peptide presentation and T cell recognition. Similar to HLA-A*0101, which is one of the earliest identified HLA alleles among the human population, HLA-A*2601 possesses a similar characteristic for the binding peptide and acts as a prevalent allomorph in HLA-I. In this study, we found that, compared with HLA-A*0101, HLA-A*2601 individuals exhibit distinctive features for the T cell responses to SARS-CoV-2 and influenza virus after infection and/or vaccination. The heterogeneous T cell responses can be attributed to the distinct preference of HLA-A*2601 and HLA-A*0101 to T cell epitope motifs with negative-charged residues at the P1 and P3 positions, respectively. Furthermore, we determined the crystal structures of the HLA-A*2601 complexed to four peptides derived from SARS-CoV-2 and human papillomavirus, with one structure of HLA-A*0101 for comparison. The shallow pocket C of HLA-A*2601 results in the promiscuous presentation of peptides with "switchable" bulged conformations because of the secondary anchor in the median portion. Notably, the hydrogen bond network formed between the negative-charged P1 anchors and the HLA-A*2601-specific residues lead to a "closed" conformation and solid placement for the P1 secondary anchor accommodation in pocket A. This insight sheds light on the intricate relationship between HLA I allelic allomorphs, peptide binding, and the immune response and provides valuable implications for understanding disease susceptibility and potential vaccine design.
Topics: Humans; Epitopes, T-Lymphocyte; SARS-CoV-2; COVID-19; HLA-A Antigens; Peptides; Alleles; HLA-A1 Antigen
PubMed: 38885041
DOI: 10.4049/immunohorizons.2400026 -
The Israel Medical Association Journal... Jun 2024Immunoglobulin G4-related disease (IgG4-RD) is a chronic, immune-mediated condition characterized by fibro-inflammatory lesions with lymphoplasmacytic infiltration....
BACKGROUND
Immunoglobulin G4-related disease (IgG4-RD) is a chronic, immune-mediated condition characterized by fibro-inflammatory lesions with lymphoplasmacytic infiltration. Diagnosis traditionally relies on histopathological findings, including the presence of IgG4+ plasma cells. However, due to challenges in biopsy accessibility, additional measures are needed to facilitate diagnosis.
OBJECTIVES
To identify additional parameters for characterizing IgG4-RD patients.
METHODS
We compared several circulating factors between a cohort of patients with IgG4-RD disease seen at our hospital between 2017 and 2023 and healthy controls.
RESULTS
Among 16 suspected patients, 13 were confirmed to have IgG4-RD, and 3 were classified as highly likely. Comparison with controls revealed differences in white blood cell count (WBC) (Folf change (FC) 1.46, P < 0.05), plasmablasts (FC 3.76, P< 0.05), plasmablasts CD38 (FC 1.43, P < 0.05), and CD27 (FC 0.66, P = 0.054), thus highlighting potential markers for IgG4-RD diagnosis. Treatments with steroids/rituximab tend to reduce plasmablast (FC 0.6) and IgG4 (FC 0.28) levels and to increase Gal-3 levels.
CONCLUSIONS
Levels of plasmablasts are a significant diagnostic feature in IgG4-RD. Healthy individuals have a lower level of plasmablasts. Elevated Gal-3 in serum of patients with IgG4-RD suggests a role in plasmablast activation. CD38/CD27 expression by plasmablasts emerges as a potential marker. Further research on a larger cohort is needed to confirm these findings.
Topics: Humans; Immunoglobulin G4-Related Disease; Plasma Cells; Male; Female; Middle Aged; Immunoglobulin G; Biomarkers; Aged; Leukocyte Count; Case-Control Studies; Adult; Rituximab; ADP-ribosyl Cyclase 1; Tumor Necrosis Factor Receptor Superfamily, Member 7
PubMed: 38884310
DOI: No ID Found -
Journal of Pregnancy 2024There is insufficient evidence to assess the risk of the production of clinically important alloimmune irregular red blood cell (RBC) antibodies in first-time pregnant... (Comparative Study)
Comparative Study
Comparison of the Detection Rate and Specificity of Irregular Red Blood Cell Antibodies Between First-Time Pregnant Women and Women With a History of Multiple Pregnancies Among 18,010 Chinese Women.
There is insufficient evidence to assess the risk of the production of clinically important alloimmune irregular red blood cell (RBC) antibodies in first-time pregnant women. Using the microcolumn gel antiglobulin method, 18,010 Chinese women with a history of pregnancy and pregnant women were screened for irregular RBC antibodies, and for those with positive test results, antibody specificity was determined. The detection rate and specificity of irregular RBC antibodies in women with a history of multiple pregnancies (two or more) and first-time pregnant women were determined. In addition to 25 patients who passively acquired anti-D antibodies via an intravenous anti-D immunoglobulin injection, irregular RBC antibodies were detected in 121 (0.67%) of the 18,010 women. Irregular RBC antibodies were detected in 93 (0.71%) of the 13,027 women with a history of multiple pregnancies, and antibody specificity was distributed mainly in the Rh, MNSs, Lewis, and Kidd blood group systems; irregular RBC antibodies were detected in 28 (0.56%) of the 4983 first-time pregnant women, and the antibody specificity was distributed mainly in the MNSs, Rh, and Lewis blood group systems. The difference in the percentage of patients with irregular RBC antibodies between the two groups was insignificant ( = 1.248, > 0.05). Of the 121 women with irregular RBC antibodies, nine had anti-Mur antibodies, and one had anti-Di antibodies; these antibodies are clinically important but easily missed because the antigenic profile of the reagent RBCs that are commonly used in antibody screens does not include the antigens that are recognized by these antibodies. Irregular RBC antibody detection is clinically important for both pregnant women with a history of multiple pregnancies and first-time pregnant women. Mur and Di should be included in the antigenic profile of reagent RBCs that are used for performing antibody screens in the Chinese population.
Topics: Humans; Female; Pregnancy; Erythrocytes; China; Adult; Pregnancy, Multiple; Isoantibodies; Rho(D) Immune Globulin; Sensitivity and Specificity; Antibody Specificity; MNSs Blood-Group System; Asian People; Kidd Blood-Group System; East Asian People
PubMed: 38883212
DOI: 10.1155/2024/5539776 -
Frontiers in Immunology 2024CD24 is a glycosylphosphatidylinositol-anchored protein that is expressed in a wide range of tissues and cell types. It is involved in a variety of physiological and... (Review)
Review
CD24 is a glycosylphosphatidylinositol-anchored protein that is expressed in a wide range of tissues and cell types. It is involved in a variety of physiological and pathological processes, including cell adhesion, migration, differentiation, and apoptosis. Additionally, CD24 has been studied extensively in the context of cancer, where it has been found to play a role in tumor growth, invasion, and metastasis. In recent years, there has been growing interest in CD24 as a potential therapeutic target for cancer treatment. This review summarizes the current knowledge of CD24, including its structure, function, and its role in cancer. Finally, we provide insights into potential clinical application of CD24 and discuss possible approaches for the development of targeted cancer therapies.
Topics: Humans; CD24 Antigen; Neoplasms; Animals; Molecular Targeted Therapy
PubMed: 38881902
DOI: 10.3389/fimmu.2024.1401528 -
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 -
Zhongguo Fei Ai Za Zhi = Chinese... May 2024The incidence of cancer is closely correlated with age, as 75% of non-small cell lung cancer (NSCLC) patients are aged at least 65 years. The availability of immune... (Review)
Review
The incidence of cancer is closely correlated with age, as 75% of non-small cell lung cancer (NSCLC) patients are aged at least 65 years. The availability of immune checkpoint inhibitors (ICIs) has altered the available NSCLC therapeutic pattern. Limited studies on elderly patients have demonstrated that ICIs as monotherapy provide substantial benefits for patients aged 65-75 years, showing no significant difference compared to younger patients. This benefit is also observed in combination with immune-combined chemotherapy or radiotherapy. For individuals older than 75 years, the survival effect was not evident, though. Immune-related adverse events (irAEs) with ICIs alone were similar in incidence across age categories. Immune-combination chemotherapy resulted in a higher incidence of irAEs than chemotherapy alone, and patients ≥75 years of age were more likely to experience higher-grade irAEs. Besides the fact that immunosenescence in older patients influences the immune milieu in a multifaceted manner, which in turn impacts the effectiveness of immunotherapy, the prognosis is also influenced by the Eastern Cooperative Oncology Group performance status (ECOG PS) score, among other factors. For certain individuals aged ≥75 years or in poor physical health, immunotherapy combined with low-intensity chemotherapy has emerged as a viable treatment option. However, there are fewer related studies, so there should be a conscious effort to increase the number of elderly patients enrolled in the trial and a comprehensive assessment to explore individualized treatment options. To provide additional references and guidance for immunotherapy in elderly NSCLC patients and to propose new therapeutic perspectives in combination with their characteristics, this review aims to summarize and analyze the pertinent studies on the application of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors in these patients. .
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Immune Checkpoint Inhibitors; Aged; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Immunotherapy; Aged, 80 and over
PubMed: 38880924
DOI: 10.3779/j.issn.1009-3419.2024.106.10