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Journal of Thrombosis and Haemostasis :... Sep 2023Endoglin, alias CD105, is a human membrane glycoprotein highly expressed in vascular endothelial cells. It is involved in angiogenesis and angiogenesis-related diseases,... (Review)
Review
Endoglin, alias CD105, is a human membrane glycoprotein highly expressed in vascular endothelial cells. It is involved in angiogenesis and angiogenesis-related diseases, including the rare vascular pathology known as hereditary hemorrhagic telangiectasia type 1. Although endoglin acts as an accessory receptor for members of the transforming growth factor-β family, in recent years, emerging evidence has shown a novel functional role for this protein beyond the transforming growth factor-β system. In fact, endoglin has been found to be an integrin counterreceptor involved in endothelial cell adhesion processes during pathological inflammatory conditions and primary hemostasis. Furthermore, a circulating form of endoglin, also named as soluble endoglin, whose levels are abnormally increased in different pathological conditions, such as preeclampsia, seems to act as an antagonist of membrane-bound endoglin and as a competitor of the fibrinogen-integrin interaction in platelet-dependent thrombus formation. These studies suggest that membrane-bound endoglin and circulating endoglin are important components involved in vascular homeostasis and hemostasis.
Topics: Female; Humans; Pregnancy; Antigens, CD; Endoglin; Endothelial Cells; Integrins; Receptors, Cell Surface; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta; Transforming Growth Factors; Vascular Cell Adhesion Molecule-1
PubMed: 37315795
DOI: 10.1016/j.jtha.2023.06.007 -
Proceedings of the National Academy of... Dec 2023Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that...
Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8 T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8 T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by -depletion were CD8 T cell- and MHC-I-dependent, as CD8 T cell depletion or knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.
Topics: Mice; Animals; Humans; CD8-Positive T-Lymphocytes; Genes, MHC Class I; Histocompatibility Antigens Class I; Immunotherapy; Lipids; Neoplasms
PubMed: 38011559
DOI: 10.1073/pnas.2314416120 -
Frontiers in Immunology 2023Chondroitin sulfate proteoglycan 4 (CSPG4), also known as high molecular weight-melanoma associated antigen, is expressed in melanoma but also other tumor entities and...
INTORDUCTION
Chondroitin sulfate proteoglycan 4 (CSPG4), also known as high molecular weight-melanoma associated antigen, is expressed in melanoma but also other tumor entities and constitutes an attractive target for immunotherapeutic approaches. While recent preclinical reports focused on anti-CSPG4 chimeric antigen receptors (CAR), we here explore T-cell receptor (TCR)-based approaches targeting CSPG4.
METHODS
The TCRs of two CSPG4-reactive T-cell clones (11C/73 and 2C/165) restricted by the highly prevalent HLA-C*07:01 allele were isolated and the respective αβTCR pairs were retrovirally expressed in CRISPR/Cas9-edited TCR-knockout T cells for functional testing. We also combined alpha and beta TCR chains derived from 11C/73 and 2C/165 in a cross-over fashion to assess for hemichain dominance. CSPG4 melanoma, glioblastoma and lung cancer cell lines were identified and, if negative, retrovirally transduced with HLA-C*07:01.
RESULTS
Functional tests confirmed specific recognition of CSPG4HLA-C*07:01 target cells by the αβTCR retrieved from the parental T-cell clones and in part also by the cross-over TCR construct 2Cα-11Cβ. Despite high surface expression, the 11Cα-2Cβ combination, however, was not functional.
DISCUSSION
Collectively, 11C/73- and 2C/165-expressing T cells specifically and efficiently recognized CSPG4HLA-C*07:01 cancer cells which warrants further preclinical and clinical evaluation of these TCRs.
Topics: Humans; HLA-C Antigens; Receptors, Antigen, T-Cell; Melanoma; T-Lymphocytes; Membrane Proteins; Chondroitin Sulfate Proteoglycans
PubMed: 37849763
DOI: 10.3389/fimmu.2023.1245559 -
The Journal of Experimental Medicine Jul 2023CD28 and CTLA4 are T cell coreceptors that competitively engage B7 ligands CD80 and CD86 to control adaptive immune responses. While the role of CTLA4 in restraining...
CD28 and CTLA4 are T cell coreceptors that competitively engage B7 ligands CD80 and CD86 to control adaptive immune responses. While the role of CTLA4 in restraining CD28 costimulatory signaling is well-established, the mechanism has remained unclear. Here, we report that human T cells acquire antigen-presenting-cell (APC)-derived B7 ligands and major histocompatibility complex (MHC) via trogocytosis through CD28:B7 binding. Acquired MHC and B7 enabled T cells to autostimulate, and this process was limited cell-intrinsically by CTLA4, which depletes B7 ligands trogocytosed or endogenously expressed by T cells through cis-endocytosis. Extending this model to the previously proposed extrinsic function of CTLA4 in human regulatory T cells (Treg), we show that blockade of either CD28 or CTLA4 attenuates Treg-mediated depletion of APC B7, indicating that trogocytosis and CTLA4-mediated cis-endocytosis work together to deplete B7 from APCs. Our study establishes CTLA4 as a cell-intrinsic molecular sink that limits B7 availability on the surface of T cells, with implications for CTLA4-targeted therapy.
Topics: Humans; CTLA-4 Antigen; CD28 Antigens; Antigens, CD; Ligands; Antigens, Differentiation; Abatacept; B7-2 Antigen; Membrane Glycoproteins; Immunoconjugates; B7-1 Antigen; Cell Adhesion Molecules
PubMed: 37042938
DOI: 10.1084/jem.20221391 -
Advanced Science (Weinheim,... Apr 2024The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related...
The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several cell surface receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remain poorly understood. Here, it is shown that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF but not the monomer of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. These results identify neuronal Lag3 as a receptor of pathologic Tau in the brain,and for AD and related Tauopathies, a therapeutic target.
Topics: Animals; Humans; Mice; Alzheimer Disease; Antigens, CD; Disease Models, Animal; Lymphocyte Activation Gene 3 Protein; Neurons; tau Proteins; Tauopathies
PubMed: 38327094
DOI: 10.1002/advs.202303775 -
Journal For Immunotherapy of Cancer Sep 2023Tumor-specific mutated proteins can create immunogenic non-self, mutation-containing 'neoepitopes' that are attractive targets for adoptive T-cell therapies. To avoid...
BACKGROUND
Tumor-specific mutated proteins can create immunogenic non-self, mutation-containing 'neoepitopes' that are attractive targets for adoptive T-cell therapies. To avoid the complexity of defining patient-specific, private neoepitopes, there has been major interest in targeting common shared mutations in driver genes using off-the-shelf T-cell receptors (TCRs) engineered into autologous lymphocytes. However, identifying the precise naturally processed neoepitopes to pursue is a complex and challenging process. One method to definitively demonstrate whether an epitope is presented at the cell surface is to elute peptides bound to a specific major histocompatibility complex (MHC) allele and analyze them by mass spectrometry (MS). These MS data can then be prospectively applied to isolate TCRs specific to the neoepitope.
METHODS
We created mono-allelic cell lines expressing one class I HLA allele and one common mutated oncogene in order to eliminate HLA deconvolution requirements and increase the signal of recovered peptides. MHC-bound peptides on the surface of these cell lines were immunoprecipitated, purified, and analyzed using liquid chromatography-tandem mass spectrometry, producing a list of mutation-containing minimal epitopes. To validate the immunogenicity of these neoepitopes, HLA-transgenic mice were vaccinated using the minimal peptides identified by MS in order to generate neoepitope-reactive TCRs. Specificity of these candidate TCRs was confirmed by peptide titration and recognition of transduced targets.
RESULTS
We identified precise neoepitopes derived from mutated isoforms of KRAS, EGFR, BRAF, and PIK3CA presented by HLA-A*03:01 and/or HLA-A*11:01 across multiple biological replicates. From our MS data, we were able to successfully isolate murine TCRs that specifically recognize four HLA-A*11:01 restricted neoepitopes (KRAS G13D, PIK3CA E545K, EGFR L858R and BRAF V600E) and three HLA-A*03:01 restricted neoepitopes (KRAS G12V, EGFR L858R and BRAF V600E).
CONCLUSIONS
Our data show that an MS approach can be used to demonstrate which shared oncogene-derived neoepitopes are processed and presented by common HLA alleles, and those MS data can rapidly be used to develop TCRs against these common tumor-specific antigens. Although further characterization of these neoepitope-specific murine TCRs is required, ultimately, they have the potential to be used clinically for adoptive cell therapy.
Topics: Humans; Mice; Animals; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Neoplasms; Antigens, Neoplasm; Histocompatibility Antigens; Receptors, Antigen, T-Cell; Peptides; Epitopes; Neoplasm Proteins; HLA-A Antigens; ErbB Receptors
PubMed: 37758652
DOI: 10.1136/jitc-2023-007097 -
Frontiers in Immunology 2024While observational studies link immune cells with post-stroke functional outcome, the underlying immune mechanisms are not well understood. Immune cell surface antigens...
OBJECTIVE
While observational studies link immune cells with post-stroke functional outcome, the underlying immune mechanisms are not well understood. Immune cell surface antigens are actively involved in the biological behavior of immune cells, investigating immune cell surface antigens could deepen our comprehension of their role and biological processes in stroke recovery. Therefore, we aimed to investigate the immunological basis of stroke outcome by exploring the causal relationship between immune cell surface antigens and functional outcome after ischemic stroke in a Mendelian randomization study.
METHODS
Genetic variants related to immune cell surface antigens and post-stroke functional outcome were selected for two-sample Mendelian randomization (MR) analysis. 389 fluorescence intensities (MFIs) with surface antigens were included. Inverse variance weighted (IVW) modeling was used as the primary MR method to estimate the causal effect of exposure on the outcome, followed by several alternative methods and sensitivity analyses. Additional analysis of the association between immune cell surface antigens and risk of ischemic stroke for assessment of collider bias.
RESULTS
We found that suggestive associations between CD20 on switched memory B cell (OR = 1.16, 95% CI: 1.01-1.34, p 0.036) and PDL-1 on monocyte (OR = 1.32, 95% CI: 1.04-1.66, p = 0.022) and poor post-stroke functional outcome, whereas CD25 on CD39+ resting Treg (OR = 0.77, 95% CI: 0.62-0.96, p = 0.017) was suggestively associated with good post-stroke functional outcome.
CONCLUSION
The elevated CD20 on switched memory B cell, PDL-1 on monocyte, and CD25 on CD39+ resting Treg may be novel biomarkers and potential causal factors influencing post-stroke functional outcome.
Topics: Humans; Ischemic Stroke; Mendelian Randomization Analysis; Stroke; Antigens, Surface; Causality
PubMed: 38562935
DOI: 10.3389/fimmu.2024.1353034 -
Clinical and Experimental Rheumatology Jan 2024To assess the expression of age-associated B cells (ABCs), and characterise the surface markers of ABCs in patients with IgG4-related disease (IgG4-RD).
OBJECTIVES
To assess the expression of age-associated B cells (ABCs), and characterise the surface markers of ABCs in patients with IgG4-related disease (IgG4-RD).
METHODS
Fifty-one newly diagnosed patients with IgG4-RD, 18 IgG4-RD patients with disease remission, 34 patients with other autoimmune diseases, and 61 age- and sex-matched healthy controls (HCs) were included. Circulating ABCs, as well as surface markers were detected by flow cytometry, and tissue infiltration of ABCs were assessed by immunofluorescence (IF). The expression of ABCs in the affected organs of LatY136F knock-in (LAT) mouse models (IgG4-RD mouse model) were explored by flow cytometry and IF.
RESULTS
The percentages and absolute numbers of ABCs (gated as CD21-T-bet+CD11c+) in CD19+ B cells raised remarkably in untreated IgG4-RD patients than HC, and reduced significantly after treatment. The percentage of CD27+ABCs, DN2 B cells and activated naive B cells was higher in patients with IgG4-RD than in HCs and patients with multiple autoimmune diseases, whereas the percentage was comparable with that in patients with systemic lupus erythematosus. Phenotypical analysis revealed upregulated levels of CD86, TACI, CD38, and downregulated level of CXCR3 in peripheral CD19+CD21-CD11c+ B cells of IgG4-RD patients compared with that of HC. In IgG4-RD patients, CD19+CD21- CD11c+ cells expressed higher levels of CD80, CXCR3, TACI, CD95, and BAFF-R, while lower levels of CD86, CD27, CD38, and CXCR5 compared with CD19+ CD21- CD11c- B cells. ABCs (CD11c+T-bet+ gated in B220+ cells) were increased significantly in lungs of LAT mice than that of wild type (WT) mice.
CONCLUSIONS
ABCs were expanded both in the peripheral blood and affected tissues of patients with IgG4-RD as well as in the lungs of LAT mice, indicating the potential roles of ABCs in IgG4-RD pathogenesis.
Topics: Humans; Animals; Mice; Immunoglobulin G4-Related Disease; B-Lymphocytes; Autoimmune Diseases; Flow Cytometry; Lupus Erythematosus, Systemic; Antigens, CD19
PubMed: 37470223
DOI: 10.55563/clinexprheumatol/1b9d13 -
Frontiers in Immunology 2023The immune checkpoint molecules programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) are one of the most promising targets for tumor... (Review)
Review
The immune checkpoint molecules programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) are one of the most promising targets for tumor immunotherapy. PD-L1 is overexpressed on the surface of tumor cells and inhibits T cell activation upon binding to PD⁃1 on the surface of T cells, resulting in tumor immune escape. The therapeutic strategy of targeting PD-1/PD-L1 involves blocking this binding and restoring the tumor-killing effect of immune cells. However, in clinical settings, a relatively low proportion of cancer patients have responded well to PD-1/PD-L1 blockade, and clinical outcomes have reached a bottleneck and no substantial progress has been made. In recent years, PD-L1 post-translation modifications (PTMs) have gradually become a hot topic in the field of PD-L1 research, which will provide new insights to improve the efficacy of current anti-PD-1/PD-L1 therapies. Here, we summarized and discussed multiple PTMs of PD-L1, including glycosylation, ubiquitination, phosphorylation, acetylation and palmitoylation, with a major emphasis on mechanism-based therapeutic strategies (including relevant enzymes and targets that are already in clinical use and that may become drugs in the future). We also summarized the latest research progress of PTMs of PD-L1/PD-1 in regulating immunotherapy. The review provided novel strategies and directions for tumor immunotherapy research based on the PTMs of PD-L1/PD-1.
Topics: Humans; B7-H1 Antigen; Neoplasms; Protein Processing, Post-Translational; Immunotherapy
PubMed: 37554324
DOI: 10.3389/fimmu.2023.1230135 -
Scientific Reports Aug 2023Oncogenic cell-surface membrane proteins contribute to the phenotypic and functional characteristics of cancer stem cells (CSCs). We employed a proximity-labeling...
Oncogenic cell-surface membrane proteins contribute to the phenotypic and functional characteristics of cancer stem cells (CSCs). We employed a proximity-labeling proteomic approach to quantitatively analyze the cell-surface membrane proteins in close proximity to CD147 in CSCs. Furthermore, we compared CSCs to non-CSCs to identify CSC-specific cell-surface membrane proteins that are closely interact with CD147 and revealed that lateral interaction between CD147 and CD276 concealed within the lipid raft microdomain in CSCs, confers resistance to docetaxel, a commonly used chemotherapy agent for various cancer types, including metastatic breast cancer. Moreover, we investigated the clinical relevance of CD147 and CD276 co-expression in HER2+ breast cancer (BC) and triple-negative breast cancer patients who underwent chemotherapy. We observed poor disease-free survival and Overall survival rates in patients of CD147 and CD276 (p = 0.04 and 0.08, respectively). Subsequent immunohistochemical analysis in independent cohorts of HER2+ BC support for the association between co-expression of CD147 and CD276 and a poor response to chemotherapy. Collectively, our study suggests that the lateral interaction between CD147 and its proximal partners, such as CD276, may serve as a poor prognostic factor in BC and a predictive marker for the critical phenotypic determinant of BC stemness.
Topics: Humans; Proteome; Proteomics; Triple Negative Breast Neoplasms; Docetaxel; Membrane Proteins; Transcription Factors; B7 Antigens
PubMed: 37648771
DOI: 10.1038/s41598-023-41416-7