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Cellular Immunology Dec 2022Major histocompatibility complex (MHC-I) peptide antigen processing and presentation has experienced a revived interest in the context of immuno oncology, immune...
Major histocompatibility complex (MHC-I) peptide antigen processing and presentation has experienced a revived interest in the context of immuno oncology, immune surveillance escape by pathogen mutations and technical advances that accelerate vaccine design. This sheds new light on the discoveries made by Nilabh Shastri and colleagues that includes the characterisation of cryptic MHC-I peptide antigen epitopes derived from untranslated regions and the N-terminal trimming of peptide antigen precursors by the aminopeptidase ERAAP (ERAP1/2 / ARTS1/LRAP) in the endoplasmic reticulum (ER) prior to the complete assembly of MHC-I complexes and their subsequent exposure to the cell surface. These scientific findings have important implications for developing novel therapeutic approaches in immunotherapy and modern vaccine design.
Topics: Antigen Presentation; Histocompatibility Antigens Class I; Peptides; Major Histocompatibility Complex; Vaccines
PubMed: 36371991
DOI: 10.1016/j.cellimm.2022.104638 -
Frontiers in Immunology 2021Endometriosis is an oestrogen-dependent chronic inflammatory process with primary symptoms including dysmenorrhea, chronic pelvic pain, and infertility. The immune...
Endometriosis is an oestrogen-dependent chronic inflammatory process with primary symptoms including dysmenorrhea, chronic pelvic pain, and infertility. The immune environment of the endometrium is essential for successful embryo implantation and ongoing pregnancy. In this study, we assessed the composition, density, and distribution of infiltrating immune cells in the endometria of women with endometriosis. Gene expression profiles of endometrial samples were downloaded from the Gene Expression Omnibus (GEO) database. We found that the TNF signalling pathway, the IL-17 signalling pathway, and the MAPK signalling pathway were significantly enriched in the eutopic endometria of women with endometriosis. The fractions and proportion of infiltrating immune cells were estimated by the CIBERSORT, MCP-counter, and ImmuCellAI methods. We found that the proportions of CD8 T cells, activated NK cells, and follicular helper T cells were significantly higher in the endometria of women with endometriosis than in the endometria of normal controls, while the proportions of M2 macrophages and resting mast cells were significantly lower in the eutopic endometria. In GSE120103 (n = 36), we found that elevated CD8 T cells in endometriosis increased the risk of infertility (P = 0.0019). The area under the receiver operating characteristic (ROC) curve (AUC) of CD8 T cells to distinguish fertile and infertile endometriosis was 0.914. In clinical samples (n = 40), we found that the proportions of CD8 T cells and CD56 NK cells were significantly higher in the eutopic endometria of women with endometriosis than in the endometria of normal controls, while the proportion of CD163 macrophages were lower in the eutopic endometria. The AUCs of CD8 T cells and CD163 macrophages were 0.727 and 0.833, respectively, which indicated that CD8 and CD163 were potential diagnostic markers for endometriosis. In conclusion, our results demonstrated that increased CD8 T cells and CD56 NK cells and decreased CD163 macrophages within the eutopic endometria of women with endometriosis reveal a proinflammatory feature in the endometrial immune environment and that elevated CD8 T cells increase the risk of infertility in women with the disease.
Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; CD56 Antigen; CD8 Antigens; CD8-Positive T-Lymphocytes; Cell Movement; Cells, Cultured; Databases, Factual; Endometriosis; Endometrium; Female; Humans; Inflammation; Killer Cells, Natural; Macrophages; Receptors, Cell Surface
PubMed: 34539624
DOI: 10.3389/fimmu.2021.671201 -
European Journal of Nuclear Medicine... Dec 2021This review discusses the current state of prostate-specific membrane antigen (PSMA)-based alpha therapy of metastatic castration-resistant prostate cancer (mCRPC). With... (Review)
Review
PURPOSE
This review discusses the current state of prostate-specific membrane antigen (PSMA)-based alpha therapy of metastatic castration-resistant prostate cancer (mCRPC). With this in-depth discussion on the growing field of PSMA-based alpha therapy (PAT), we aimed to increase the interactions between basic scientists and physician-scientists in order to advance the field.
METHODS
To achieve this, we discuss the potential, current status, and opportunities for alpha therapy and strategies, attempted to date, and important questions that need to be addressed. The paper reviews important concepts, including whom to treat, how to treat, what to expect regarding treatment outcome, and toxicity, and areas requiring further investigations.
RESULTS
There is much excitement about the potential of this field. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other conventional therapies.
CONCLUSION
A better understanding of the strengths and limitations of PAT may help in creating an effective therapy for mCRPC and design a rational combinatorial approach to treatment by targeting different tumor pathways.
Topics: Antigens, Surface; Glutamate Carboxypeptidase II; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome
PubMed: 34173838
DOI: 10.1007/s00259-021-05434-9 -
Current Opinion in Immunology Jun 2023The expression of MHC-II and CD86 on the surface of antigen-presenting cells (APCs) must be tightly regulated to foster antigen-specific CD4 T-cell activation and to... (Review)
Review
The expression of MHC-II and CD86 on the surface of antigen-presenting cells (APCs) must be tightly regulated to foster antigen-specific CD4 T-cell activation and to prevent autoimmunity. Surface expression of these proteins is regulated by their dynamic ubiquitination by the E3 ubiquitin ligase March-I. March-I promotes turnover of peptide-MHC-II complexes on resting APCs and termination of March-I expression promotes MHC-II and CD86 surface stability. In this review, we will highlight recent studies examining March-I function in both normal and pathological conditions.
Topics: Humans; Histocompatibility Antigens Class II; Ubiquitination; Antigen-Presenting Cells; Ubiquitin-Protein Ligases; CD4-Positive T-Lymphocytes
PubMed: 37075597
DOI: 10.1016/j.coi.2023.102325 -
Journal of Virology Dec 2022Hepatitis B virus (HBV) is a major risk factor for serious liver diseases. The liver plays a unique role in controlling carbohydrate metabolism to maintain the glucose...
Hepatitis B virus (HBV) is a major risk factor for serious liver diseases. The liver plays a unique role in controlling carbohydrate metabolism to maintain the glucose level within the normal range. Chronic HBV infection has been reported to associate with a high prevalence of diabetes. However, the detailed molecular mechanism underlying the potential association remains largely unknown. Here, we report that liver-targeted delivery of small HBV surface antigen (SHBs), the most abundant viral protein of HBV, could elevate blood glucose levels and impair glucose and insulin tolerance in mice by promoting hepatic gluconeogenesis. Hepatocytes with SHB expression also exhibited increased glucose production and expression of gluconeogenic genes () and () in response to glucagon stimulation. Mechanistically, SHBs increased cellular levels of cyclic AMP (cAMP) and consequently activated protein kinase A (PKA) and its downstream effector cAMP-responsive element binding protein (CREB). SHBs-induced activation of CREB enhanced transcripts of gluconeogenic genes, thus promoting hepatic gluconeogenesis. The elevated cAMP level resulted from increased transcription activity and expression of adenylyl cyclase 1 (AC1) by SHBs through a binary E-box factor binding site (BEF). Taken together, we unveiled a novel pathogenic role and mechanism of SHBs in hepatic gluconeogenesis, and these results might highlight a potential target for preventive and therapeutic intervention in the development and progression of HBV-associated diabetes. Chronic HBV infection causes progressive liver damage and is found to be a risk factor for diabetes. However, the mechanism in the regulation of glucose metabolism by HBV remains to be established. In the current study, we demonstrate for the first time that the small hepatitis B virus surface antigen (SHBs) of HBV elevates AC1 transcription and expression to activate cAMP/PKA/CREB signaling and subsequently induces the expression of gluconeogenic genes and promotes hepatic gluconeogenesis both and . This study provides a direct link between HBV infection and diabetes and implicates that SHBs may represent a potential target for the treatment of HBV-induced metabolic disorders.
Topics: Animals; Mice; Antigens, Surface; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Glucagon; Gluconeogenesis; Glucose; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Liver; Mice, Inbred C57BL
PubMed: 36394315
DOI: 10.1128/jvi.01020-22 -
ELife Oct 2021B-cell receptor (BCR)-mediated antigen internalization and presentation are essential for humoral memory immune responses. Antigen encountered by B-cells is often...
B-cell receptor (BCR)-mediated antigen internalization and presentation are essential for humoral memory immune responses. Antigen encountered by B-cells is often tightly associated with the surface of pathogens and/or antigen-presenting cells. Internalization of such antigens requires myosin-mediated traction forces and extracellular release of lysosomal enzymes, but the mechanism triggering lysosomal exocytosis is unknown. Here, we show that BCR-mediated recognition of antigen tethered to beads, to planar lipid-bilayers or expressed on cell surfaces causes localized plasma membrane (PM) permeabilization, a process that requires BCR signaling and non-muscle myosin II activity. B-cell permeabilization triggers PM repair responses involving lysosomal exocytosis, and B-cells permeabilized by surface-associated antigen internalize more antigen than cells that remain intact. Higher affinity antigens cause more B-cell permeabilization and lysosomal exocytosis and are more efficiently presented to T-cells. Thus, PM permeabilization by surface-associated antigen triggers a lysosome-mediated B-cell resealing response, providing the extracellular hydrolases that facilitate antigen internalization and presentation.
Topics: Animals; Antigen Presentation; Antigens, Surface; B-Lymphocytes; Cell Line; Cell Membrane; Exocytosis; Lysosomes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Permeability; Receptors, Antigen, B-Cell; T-Lymphocytes
PubMed: 34704555
DOI: 10.7554/eLife.66984 -
Bioconjugate Chemistry Jul 2022Auger electron therapy exploits the cytotoxicity of low-energy electrons emitted during radioactive decay that travel very short distances (typically <1 μm). Tl, with a...
Auger electron therapy exploits the cytotoxicity of low-energy electrons emitted during radioactive decay that travel very short distances (typically <1 μm). Tl, with a half-life of 73 h, emits ∼37 Auger and other secondary electrons per decay and can be tracked as its gamma emissions enable SPECT imaging. Despite the useful nuclear properties of Tl, satisfactory bifunctional chelators to incorporate it into bioconjugates for molecular targeting have not been developed. Hpypa, Hdecapa, Hneunpa-NH, and Hnoneunpa are multidentate N- and O-donor chelators that have previously been shown to have high affinity for In, Lu, and Zr. Herein, we report the synthesis and serum stability of [Tl]Tl complexes with Hpypa, Hdecapa, Hneunpa-NH, and Hnoneunpa. All ligands quickly and efficiently formed complexes with [Tl]Tl that gave simple single-peak radiochromatograms and showed greatly improved serum stability compared to DOTA and DTPA. [Tl]Tl-pypa was further characterized using nuclear magnetic resonance spectroscopy (NMR), mass spectroscopy (MS), and X-ray crystallography, showing evidence of the proton-dependent presence of a nine-coordinate complex and an eight-coordinate complex with a pendant carboxylic acid group. A prostate-specific membrane antigen (PSMA)-targeting bioconjugate of Hpypa was synthesized and radiolabeled. The uptake of [Tl]Tl-pypa-PSMA in DU145 PSMA-positive and PSMA-negative prostate cancer cells was evaluated and showed evidence of bioreductive release of Tl and cellular uptake characteristic of unchelated [Tl]TlCl. SPECT/CT imaging was used to probe the biodistribution and stability of [Tl]Tl-pypa-PSMA. In healthy animals, [Tl]Tl-pypa-PSMA did not show the myocardial uptake that is characteristic of unchelated Tl. In mice bearing DU145 PSMA-positive and PSMA-negative prostate cancer xenografts, the uptake of [Tl]Tl-pypa-PSMA in DU145 PSMA-positive tumors was higher than that in DU145 PSMA-negative tumors but insufficient for useful tumor targeting. We conclude that Hpypa and related ligands represent an advance compared to conventional radiometal chelators such as DOTA and DTPA for Tl chelation but do not resist dissociation for long periods in the biological environment due to vulnerability to reduction of Tl and subsequent release of Tl. However, this is the first report describing the incorporation of [Tl]Tl into a chelator-peptide bioconjugate and represents a significant advance in the field of Tl-based radiopharmaceuticals. The design of the next generation of chelators must include features to mitigate this susceptibility to bioreduction, which does not arise for other trivalent heavy radiometals.
Topics: Animals; Antigens, Surface; Cell Line, Tumor; Chelating Agents; Glutamate Carboxypeptidase II; Humans; Male; Mice; Nuclear Medicine; Pentetic Acid; Prostatic Neoplasms; Radiopharmaceuticals; Thallium Radioisotopes; Tissue Distribution
PubMed: 35801668
DOI: 10.1021/acs.bioconjchem.2c00284 -
Oncoimmunology 2023The expression of viral antigens in chronic hepatitis B virus (HBV) infection drives continuous liver inflammation, one of the main risk factors to develop liver cancer....
The expression of viral antigens in chronic hepatitis B virus (HBV) infection drives continuous liver inflammation, one of the main risk factors to develop liver cancer. HBV developed immune-suppressive functions to escape from the host immune system, but their link to liver tumor development is not well understood. Here, we analyzed if and how HBV surface antigen (HBs) expression in combined hepatocellular-cholangiocarcinoma (cHCC/iCCA) cells influences their antigenicity for CD8 T cells. We randomly isolated liver tumor tissues from AlfpCre-Trp53/Alb-HBs tg mice and established primary carcinoma cell lines (pCCL) that showed a bilineal (CK7/HNF4α) cHCC/iCCA phenotype. These pCCL uniformly expressed HBs (HBs), and low levels of MHC-I (MHC-I), and were transiently convertible to a high antigenicity (MHC-I) phenotype by IFN-γ treatment. HBs/pCCL induced HBs/(K/S)-specific CD8 T cells and developed slow-growing tumors in subcutaneously transplanted C57Bl/6J (B6) mice. Interestingly, pCCL-ex cells, established from HBs/pCCL-induced and re-explanted tumors in B6 but not those in immune-deficient Rag1 mice showed major alterations, like an MHC-I phenotype, a prominent growth-biased gene expression signature, a significantly decreased HBs expression (HBs) and a switch to fast-growing tumors in re-transplanted B6 or PD-1 hosts with an unlocked PD-1/PD-L1 control system. CD8 T cell-mediated elimination of HBs/pCCL, together with the attenuation of the negative restraints of HBs in the tumor cells, like ER-stress, reveals a novel mechanism to unleash highly aggressive HBs/pCCL-ex immune-escape variants. Under certain conditions, HBs-specific CD8 T-cell responses thus potentiate tumor growth, an aspect that should be considered for therapeutic vaccination strategies against chronic HBV infection and liver tumors.
Topics: Mice; Animals; Hepatitis B, Chronic; Hepatitis B virus; Programmed Cell Death 1 Receptor; CD8-Positive T-Lymphocytes; Cell Line; Liver Neoplasms; Carcinoma
PubMed: 37261086
DOI: 10.1080/2162402X.2023.2215096 -
Viruses Nov 2022Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying...
Clinical Outcomes and Quantitative HBV Surface Antigen Levels in Diverse Chronic Hepatitis B Patients in Canada: A Retrospective Real-World Study of CHB in Canada (REVEAL-CANADA).
BACKGROUND
Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying HBsAg levels on clinical outcomes in diverse cohorts are understudied.
METHODS
In this cross-sectional, multicentre, retrospective study, the data on adult subjects enrolled in the Canadian HBV Network with CHB seen from 1 January 2012 to 30 January 2021 with the treatment and virologic data within 1 year of HBsAg testing were analyzed. Patients were tested for HBsAg using qualitative (for HBsAg-negative samples) and/or commercial quantitative assays. Fibrosis or hepatic necroinflammation was determined by the liver stiffness measurement (LSM). The baseline data were summarized using descriptive statistics and compared by using univariable/multivariable analyses.
RESULTS
This study included 844 CHB patients, with a median age of 49.6 years (IQR 40.1-60.5), and 37% were female. In total, 751 patients (78.6%) had known ethnicity data, and 76.7% self-reported as Asian, 11.4% as Black, 6.8% as White, and 4.8% as other. Among the 844 patients, 237 (28.0%) were HBsAg (-) (
1000 IU/mL. Overall, 80% (682) had known HBeAg status at the last follow-up, and the majority (87.0%) were HBeAg-negative. In addition, 54% (461/844) had prior antiviral therapy, 19.7% of which (16.3, 23.7, = 91) were HBsAg (-). The treated patients had a lower risk of cirrhosis (16.46, 95% CI 1.89-143.39, = 0.01) or HCC (8.23, 95% CI 1.01-67.39, = 0.05) than the untreated patients. A lower proportion of the HBsAg-loss group had cirrhosis (5.7% vs. 10.9%, = 0.021) and HCC (0.9% vs. 6.2%, = 0.001). CONCLUSION
In this retrospective, ethnically diverse cohort study, CHB patients who received antiviral therapy and/or had HBsAg loss were less likely to develop cirrhosis and HCC, confirming the results of the studies in less diverse cohorts. No association was found between the qHBsAg level and fibrosis determined with LSM. Individuals who achieved HBsAg loss had low-level qHBsAg within 1 year of seroclearance.
Topics: Adult; Humans; Female; Middle Aged; Male; Hepatitis B, Chronic; Hepatitis B Surface Antigens; Hepatitis B virus; Retrospective Studies; Hepatitis B e Antigens; Antigens, Surface; Cohort Studies; Cross-Sectional Studies; Carcinoma, Hepatocellular; Canada; Liver Neoplasms; Antiviral Agents; Liver Cirrhosis; DNA, Viral
PubMed: 36560672
DOI: 10.3390/v14122668 -
Chemical & Pharmaceutical Bulletin 2020Bone metastases can cause high morbidity and mortality, often developing as they advance, especially in patients with prostate and breast cancers. Most drugs are rarely... (Review)
Review
Bone metastases can cause high morbidity and mortality, often developing as they advance, especially in patients with prostate and breast cancers. Most drugs are rarely distributed to the bone and are hence pharmacologically ineffective in treating bone metastases. The development of drug targeting technologies is required for the efficient treatment of bone metastases. To date, numerous bone-targeting ligands, including tetracyclines, bisphosphonates, aspartic acid, and aptamers have been developed and used for bone-targeted delivery of anti-tumor drugs, peptide/protein drugs, nucleic acid drugs, and diagnostic imaging agents. The conjugates of drugs with bone-targeting ligands were first developed in the field of bone drug targeting systems; macromolecular carriers and nanoparticles modified with these bone-targeting ligands have also been developed. Additionally, antibodies to prostate-specific membrane antigen (PSMA) and human epidermal growth factor receptor 2 (HER2) are used in active targeting bone metastatic prostate cancer and breast cancer, respectively. Some conjugates using antibodies to PSMA and HER2 were developed and used in clinical trials. In this review, recent challenges in the development of bone-targeted delivery systems and strategies for the treatment of bone metastasis have been summarized. Future development of novel drug formulations in order to optimize targeted drug delivery in the treatment of bone metastasis have also been discussed.
Topics: Animals; Antigens, Surface; Antineoplastic Agents; Bone Neoplasms; Drug Delivery Systems; Glutamate Carboxypeptidase II; Humans; Ligands; Molecular Structure; Receptor, ErbB-2
PubMed: 32611993
DOI: 10.1248/cpb.c20-00017