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Carcinogenesis Dec 2022Tumor cell surface antigen recognition is a major hallmark of cancer therapy, and loss of major histocompatibility complex class I (MHC-I) is the most common mechanism...
Tumor cell surface antigen recognition is a major hallmark of cancer therapy, and loss of major histocompatibility complex class I (MHC-I) is the most common mechanism that impairs tumor cell surface antigen processing and expression. In addition to this, MHC-II regulates antigen presentation in CD4+ T cell immune responses involved in tumor killing by CD8+ T cells, whereas the regulation of endocytosis regulating MHC-II antigen presentation has not been reported. Therefore, the regulation of the endocytosis pathway on the expression of MHC-II surface level and antitumor T cell response remains to be explored. In this experiment, we found that LAMTOR1 regulates the endocytic pathway through the GTPase domain of DNM2 and triggers the formation of autophagosomes. We performed flow cytometry and western blotting analyses, which revealed that the expression of MHC-II molecules on the surface of cells is influenced by LAMTOR1 through the endocytic pathway. We showed that the expression of MHC-II molecules, which recognize CD4+ T cells on the surface of cells, was regulated by LAMTOR1 through an endocytic pathway. By coculture experiments, we showed that CD8+/CD4+ T cells exhibit substantially higher levels of tumor cell apoptosis than those observed when hepatocellular carcinoma (HCC) cells were cocultured with CD8+ T cells alone. This study revealed that LAMTOR1 decreases the expression levels of MHC-II on cell surfaces in order to reduce antigen expression, leading to a decrease in antitumor T cell responses.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Histocompatibility Antigens Class II; Antigen Presentation; Histocompatibility Antigens Class I; CD4-Positive T-Lymphocytes
PubMed: 36070764
DOI: 10.1093/carcin/bgac075 -
Seminars in Cell & Developmental Biology May 2015Dendritic cells (DC) are the most potent antigen presenting cells (APC). They comprise a family of different subsets and play an essential role in the induction and... (Review)
Review
Dendritic cells (DC) are the most potent antigen presenting cells (APC). They comprise a family of different subsets and play an essential role in the induction and regulation of immune responses. Recently, gene expression profiling identified BDCA3(+)CLEC9A(+) DC as a separate human DC subset. This subset was identified in blood, where they represent the smallest population of human DC, as well as in lymphoid and peripheral tissues. This review summarizes the phenotypic, functional and developmental characteristics of BDCA3(+)CLEC9A(+) DC in relation to their mouse equivalents CD8α(+) DC and CD103(+) DC and other human DC subsets. Apart from being potent antigen presenting cells, their specialized functional capacities compared to other human DC subsets, indicate that these BDCA3(+)CLEC9A(+) DC are of major importance in the induction of anti-viral and anti-tumor immunity. Further characterization of their functional properties, developmental pathways and underlying molecular mechanisms may identify target molecules to fully exploit the immune modulatory function of BDCA3(+)CLEC9A(+) DC and potential use of these cells in immunotherapy.
Topics: Antigens, Surface; Cross-Priming; Cytokines; Dendritic Cells; Humans; Interferons; Interleukins; Lectins, C-Type; Models, Immunological; Receptors, Mitogen; Thrombomodulin
PubMed: 24910448
DOI: 10.1016/j.semcdb.2014.05.016 -
Investigative and Clinical Urology Sep 2021
Topics: Antigens, Surface; Glutamate Carboxypeptidase II; Humans; Male; Prostatic Neoplasms
PubMed: 34488249
DOI: 10.4111/icu.20210275 -
ACS Synthetic Biology Oct 2022The Notch pathway converts receptor-ligand interactions at the cell surface into a transcriptional response in the receiver cell. In recent years, synthetic Notch...
The Notch pathway converts receptor-ligand interactions at the cell surface into a transcriptional response in the receiver cell. In recent years, synthetic Notch systems (synNotch) that respond to different inputs and transduce different transcriptional responses have been engineered. One class of synNotch systems uses antibody-antigen interactions at the cell surface to induce the proteolytic cleavage cascade of the endogenous Notch autoregulatory core and the consequent release of a synNotch intracellular domain (ICD), converting surface antigen detection into a cellular response. While the activation of endogenous Notch requires ubiquitylation and subsequent endocytosis of the ligand ICD, these synNotch systems do not seem to have such a requirement because the synNotch ligands completely lack an ICD. This observation raises questions about existing models for the synNotch activation mechanism. Here, we test how different structural and biochemical factors affect the dependence of endogenous and synthetic Notch activation on ligand ICD. We compare the behavior of antibody-antigen synNotch (aa-synNotch) to that of endogenous Notch, and to a synNotch system that uses rapamycin induced dimerization of FK506 binding protein (FKBP) and FKBP rapamycin binding (FRB) domaindimerization domains (ff-synNotch), which still requires a ligand ICD. We found that differences in receptor-ligand affinity, in the identity of the transmembrane domain, or in the presence or absence of extracellular epidermal growth factor repeats cannot explain the differences in ligand ICD requirement that distinguishes aa-synNotch from endogenous Notch or ff-synNotch. We also found that unlike endogenous Notch and ff-synNotch, the aa-synNotch system does not exhibit trans-endocytosis of the receptor extracellular domain into the sender cell. These findings suggest that the aa-synNotch systems bypass the ligand ICD requirement because antigen-antibody pairs are able to promote other adhesive cell-cell interactions that provide the mechanical tension needed for ligand activation.
Topics: Ligands; Signal Transduction; Epidermal Growth Factor; Tacrolimus Binding Proteins; Sirolimus; Antigens, Surface
PubMed: 36107643
DOI: 10.1021/acssynbio.2c00247 -
Drug Development Research Dec 2021Trophoblast cell-surface antigen 2 (Trop 2) is a transmembrane glycoprotein that is highly expressed in various cancer types with relatively low or no baseline... (Review)
Review
Trophoblast cell-surface antigen 2 (Trop 2) is a transmembrane glycoprotein that is highly expressed in various cancer types with relatively low or no baseline expression in most normal tissues. Its overexpression is associated with tumor growth and poor prognosis; Trop 2 is, therefore, an ideal therapeutic target for epithelial cancers. Several Trop 2 targeted therapeutics have recently been developed for the treatment of cancers, such as anti-Trop 2 antibodies and antibody-drug conjugates (ADCs), as well as Trop 2-specific cell therapy. In particular, the safety and clinical benefit of Trop 2-based ADCs have been demonstrated in clinical trials across multiple tumor types, including those with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and heavily pretreated non-small cell lung cancer. In this review, we elaborate on recent advances in Trop 2 targeted modalities and provide an overview of novel insights for future developments in this field.
Topics: Antigens, Neoplasm; Cell Adhesion Molecules; Humans; Immunoconjugates; Immunotherapy, Adoptive; Neoplasms
PubMed: 34462935
DOI: 10.1002/ddr.21870 -
PET Clinics Jul 2017Prostate-specific membrane antigen (PSMA) has been explored as a target for molecular imaging of prostate cancer and other malignancies that express PSMA in their... (Review)
Review
Prostate-specific membrane antigen (PSMA) has been explored as a target for molecular imaging of prostate cancer and other malignancies that express PSMA in their tumor-associated neovasculature. Although several PSMA-targeted radiotracers labeled with a variety of radionuclides have been reported, positron-emitting radiotracers labeled with F are of particular interest. One such compound, the small molecule PSMA inhibitor [F]DCFPyL, has demonstrated initial success. This article reviews the literature on this radiotracer, including radiosynthetic approaches to the molecule, data that are available from preclinical experiments, and evidence to date of the clinical utility of this agent in prostate cancer and clear cell renal cell carcinoma.
Topics: Antigens, Surface; Glutamate Carboxypeptidase II; Humans; Male; Positron-Emission Tomography; Prostatic Neoplasms; Radiopharmaceuticals; Tomography, X-Ray Computed
PubMed: 28576167
DOI: 10.1016/j.cpet.2017.02.006 -
Therapeutic Drug Monitoring Apr 2016T-cell activation is a characteristic of organ rejection. T cells, located in the draining lymph nodes of the transplant recipient, are faced with non-self-molecules... (Review)
Review
T-cell activation is a characteristic of organ rejection. T cells, located in the draining lymph nodes of the transplant recipient, are faced with non-self-molecules presented by antigen presenting cells and become activated. Activated T cells are characterized by up-regulated surface antigens, such as costimulatory molecules, adhesion molecules, chemokine receptors, and major histocompatibility complex class II molecules. Surface antigen expression can be followed by flow cytometry using monoclonal antibodies in either cell function assays using donor-specific or nonspecific stimulation of isolated cells or whole blood and without stimulation on circulating lymphocytes. Molecules such as CD30 can be proteolytically cleaved off the surface of activated cells in vivo, and the determination of the soluble protein (sCD30) in serum or plasma is performed by immunoassays. As promising biomarkers for rejection and long-term transplant outcome, CD28 (costimulatory receptor for CD80 and CD86), CD154 (CD40 ligand), and sCD30 (tumor necrosis factor receptor superfamily, member 8) have been identified. Whereas cell function assays are time-consuming laboratory-developed tests which are difficult to standardize, commercial assays are frequently available for soluble proteins. Therefore, more data from clinical trials have been published for sCD30 compared with the surface antigens on activated T cells. This short review summarizes the association between selected surface antigens and immunosuppression, and rejection in solid organ transplantation.
Topics: Antigens, Surface; Biomarkers; Graft Rejection; Humans; Immunosuppression Therapy; Ki-1 Antigen; T-Lymphocytes
PubMed: 26495982
DOI: 10.1097/FTD.0000000000000259 -
Chemical Biology & Drug Design Jan 2022Prostate-specific membrane antigen (PSMA) is a glycosylated type-II transmembrane protein expressed in prostatic tissue and significantly overexpressed in several... (Review)
Review
Prostate-specific membrane antigen (PSMA) is a glycosylated type-II transmembrane protein expressed in prostatic tissue and significantly overexpressed in several prostate cancer cells. Despite its name, PSMA has also been reported to be overexpressed in endothelial cells of benign and malignant non-prostate disease. So its clinical use was extended to detection, staging, and therapy of various tumor types. Recently small molecules targeting PSMA have been developed as imaging probes for diagnosis of several malignancies. Preliminary studies are emerging improved diagnostic sensitivity and specificity of PSMA imaging, leading to a change in patient management. In this review, we evaluated the first preclinical and clinical studies on PSMA ligands resulting future perspectives radiolabeled PSMA in staging and molecular characterization, based on histopathologic examinations of PSMA expression.
Topics: Animals; Antigens, Surface; Biomarkers, Tumor; Glutamate Carboxypeptidase II; Humans; Ligands; Lung Neoplasms; Male; Positron Emission Tomography Computed Tomography; Prostatic Neoplasms; Radiopharmaceuticals
PubMed: 34472217
DOI: 10.1111/cbdd.13946 -
Genes Sep 2021Avian coccidiosis is a disease caused by members of the genus . Huge economic losses incurred by the global poultry industry due to coccidiosis have increased the need...
Avian coccidiosis is a disease caused by members of the genus . Huge economic losses incurred by the global poultry industry due to coccidiosis have increased the need for cost-effective and easily available recombinant vaccines. Microneme protein 2 (MIC2) and surface antigen 1 (SAG1) of have been recognised as potential vaccine candidates. However, the genetic diversity of the antigens in field isolates, which affects vaccine efficacy, has yet to be largely investigated. Here, we analysed genetic diversity and natural selection of and in Korean isolates. Both genes exhibited low levels of genetic diversity in Korean isolates. However, the two genes showed different patterns of nucleotide diversity and amino acid polymorphism involving the isolates obtained from different countries including China and India. These results underscore the need to investigate the genetic diversity of the vaccine candidate antigens and warrant monitoring of genetic heterogeneity and evolutionary aspects of the genes in larger numbers of field isolates from different geographical areas to design effective coccidial vaccines.
Topics: Animals; Antigens, Protozoan; Antigens, Surface; Chickens; Coccidiosis; Eimeria tenella; Female; Genetic Variation; Microneme; Poultry Diseases; Protozoan Proteins; Selection, Genetic
PubMed: 34573400
DOI: 10.3390/genes12091418 -
Viral Immunology Sep 2023This study aimed to investigate the changes of toll-like receptor 4 (TLR4), proinflammatory cytokine expression, hepatitis B virus surface antigen (HBsAg), and hepatitis...
This study aimed to investigate the changes of toll-like receptor 4 (TLR4), proinflammatory cytokine expression, hepatitis B virus surface antigen (HBsAg), and hepatitis B virus envelope antigen (HBeAg) expression as well as innate immune cell percentages in a mouse model of persistent hepatitis B virus (HBV) infection to better understand the innate immune response. Mouse models of persistent HBV infection, HBsAg expression, and HBeAg expression were developed using high-pressure tail-vein injection of recombinant adeno-associated viruses. Enzyme-linked immunosorbent assays (ELISAs) were used to determine the serum proinflammatory cytokine levels. Immunohistochemistry and western blot assays were used to detect TLR4 expression. Flow cytometric analysis was used to assess the percentage of innate immune cells in the whole blood. Persistent HBV infection, HBsAg expression, and HBeAg expression each significantly decreased the expression of TLR4. Persistent HBV infection significantly increased the percentages of T cells and monocytes, whereas it decreased the percentage of natural killer (NK) cells. Persistent HBeAg expression also decreased the percentage of NK cells, whereas persistent HBsAg expression increased the percentage of NK cells. Both persistent HBsAg and HBeAg expression increased the percentage of monocytes. However, both persistent HBsAg and HBeAg expression decreased the percentage of T cells. HBV as well as HBsAg and HBeAg showed similar effects on the expression of TLR4 and proinflammatory cytokines as well as the percentage of monocytes. Persistent HBV infection increased the percentage of T cells and decreased the percentage of NK cells, whereas only persistent HBeAg expression contributed to a decreased percentage of NK cells.
Topics: Animals; Mice; Hepatitis B virus; Hepatitis B Surface Antigens; Toll-Like Receptor 4; Hepatitis B e Antigens; Hepatitis B; Immunity, Innate; Cytokines; Disease Models, Animal; Antigens, Surface
PubMed: 37610852
DOI: 10.1089/vim.2023.0018