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Frontiers in Immunology 2019Cancer immunotherapy has made remarkable clinical advances in recent years. Antibodies targeting the immune checkpoint receptors PD-1 and CTLA-4 and adoptive cell... (Review)
Review
Cancer immunotherapy has made remarkable clinical advances in recent years. Antibodies targeting the immune checkpoint receptors PD-1 and CTLA-4 and adoptive cell therapy (ACT) based on expanded peripheral CTLs, tumor infiltrating lymphocytes (TILs), gene-engineered TCR- and chimeric antigen receptor (CAR)-T cells have all shown durable clinical efficacies in multiple types of cancers. However, these immunotherapeutic approaches only benefit a small fraction of cancer patients as various immune resistance mechanisms and limitations make their effective use a challenge in the majority of cancer patients. For example, adaptive resistance to therapeutic PD-1 blockade is associated with an upregulation of some additional immune checkpoint receptors. The efficacy of transferred tumor-specific T cells under the current clinical ACT protocol is often limited by their inefficient engraftment, poor persistence, and weak capability to attack tumor cells. Recent studies demonstrate that the complement receptor C3aR and C5aR function as a new class of immune checkpoint receptors. Complement signaling through C3aR and C5aR expressed on effector T lymphocytes prevent the production of the cytokine interleukin-10 (IL-10). Removing C3aR/C5aR-mediated transcriptional suppression of IL-10 expression results in endogenous IL-10 production by antitumor effector T cells, which drives T cell expansion and enhances T cell-mediated antitumor immunity. Importantly, preclinical, and clinical data suggest that a signaling axis consisting of complement/C3aR/C5aR/IL-10 critically regulates T cell mediated antitumor immunity and manipulation of the pathway and is an effective strategy for cancer immunotherapy. Furthermore, a combination of treatment strategies targeting the complement/C3aR/C5aR/IL-10 pathway with other treatment modalities may improve cancer therapeutic efficacy.
Topics: Animals; Humans; Immunotherapy; Interleukin-10; Lymphocytes, Tumor-Infiltrating; Neoplasms; Receptor, Anaphylatoxin C5a; Receptors, Complement
PubMed: 31379815
DOI: 10.3389/fimmu.2019.01574 -
Molecular Immunology Feb 2009Exaggerated complement activation is a key event in the pathogenesis of a range of autoimmune and inflammatory diseases. Complement Receptor 1 (CR1) has emerged as a... (Review)
Review
Exaggerated complement activation is a key event in the pathogenesis of a range of autoimmune and inflammatory diseases. Complement Receptor 1 (CR1) has emerged as a molecule of immense interest in gaining insight to the susceptibility, pathophysiology, diagnosis, prognosis and therapy of such diseases. This review brings forth a composite view of the current understanding on the structure, functions, genetics, disease associations and therapeutic implications of CR1.
Topics: Animals; Autoimmune Diseases; Humans; Inflammation; Receptors, Complement 3b
PubMed: 19004497
DOI: 10.1016/j.molimm.2008.09.026 -
The Journal of Clinical Investigation Dec 2023An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve...
An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.
Topics: Humans; Complement C5a; Receptors, Complement
PubMed: 37824211
DOI: 10.1172/JCI168277 -
Scientific Reports Jan 2023The complement system provides vital immune protection against infectious agents by labeling them with complement fragments that enhance phagocytosis by immune cells....
The complement system provides vital immune protection against infectious agents by labeling them with complement fragments that enhance phagocytosis by immune cells. Many details of complement-mediated phagocytosis remain elusive, partly because it is difficult to study the role of individual complement proteins on target surfaces. Here, we employ serum-free methods to couple purified complement C3b onto E. coli bacteria and beads and then expose human neutrophils to these C3b-coated targets. We examine the neutrophil response using a combination of flow cytometry, confocal microscopy, luminometry, single-live-cell/single-target manipulation, and dynamic analysis of neutrophil spreading on opsonin-coated surfaces. We show that purified C3b can potently trigger phagocytosis and killing of bacterial cells via Complement receptor 1. Comparison of neutrophil phagocytosis of C3b- versus antibody-coated beads with single-bead/single-target analysis exposes a similar cell morphology during engulfment. However, bulk phagocytosis assays of C3b-beads combined with DNA-based quenching reveal that these are poorly internalized compared to their IgG1 counterparts. Similarly, neutrophils spread slower on C3b-coated compared to IgG-coated surfaces. These observations support the requirement of multiple stimulations for efficient C3b-mediated uptake. Together, our results establish the existence of a direct pathway of phagocytic uptake of C3b-coated targets and present methodologies to study this process.
Topics: Humans; Neutrophils; Complement C3b; Escherichia coli; Phagocytosis; Receptors, Complement 3b; Complement System Proteins; Immunoglobulin G; Receptors, Complement
PubMed: 36609665
DOI: 10.1038/s41598-022-27279-4 -
Innate Immunity Nov 2020(PsV) is an immune-mediated inflammatory disorder with devastating psychosocial consequences. Expression of immunoregulator molecules on leukocytes in PsV remains...
(PsV) is an immune-mediated inflammatory disorder with devastating psychosocial consequences. Expression of immunoregulator molecules on leukocytes in PsV remains unclear. Leukocyte-associated Ig-like receptor-1 (LAIR-1) and complement receptor-1 (CR-1) are immunoregulator receptors reported to bind complement component 1q involved in phagocytosis. We aimed to explore if altered leukocyte expression of LAIR-1 and CR-1 is associated with PsV. This case-control study included 36 PsV patients and 36 healthy controls. Neutrophils, monocytes and B and T cells were examined by flow cytometry for LAIR-1 and CR-1 mean fluorescence intensity (MFI) and positive cell percentage. Comparison between both groups revealed a significant decrease in LAIR-1 MFI on neutrophils and T cells ( < 0.001 and = 0.003, respectively). CR-1 MFI on neutrophils, monocytes and T cells also showed a significant decrease in patients ( = 0.033, = 0.001 and = 0.040, respectively). There was a significant positive correlation of LAIR-1 MFI on neutrophils with CR-1 MFI on neutrophils ( = 0.503; = 0.002) and LAIR-1 MFI on monocytes with CR-1 MFI on monocytes ( = 0.371; = 0.026). Receiver operating characteristic curves revealed that CR-1 MFI on monocytes had the highest discrimination power to differentiate patients from controls, with 86.1% specificity and 75% sensitivity ( = 0.001). In conclusion, altered leukocytes expression of LAIR-1 and CR-1 is associated with PsV. Down-regulated CR-1 MFI on monocytes is a promising diagnostic biomarker for PsV.
Topics: Adult; Biomarkers; Case-Control Studies; Complement C1q; Female; Gene Expression Regulation; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Neutrophils; Phagocytosis; Prospective Studies; Psoriasis; Receptors, Complement; Receptors, Immunologic; T-Lymphocytes
PubMed: 32731787
DOI: 10.1177/1753425920942570 -
Glycobiology Aug 2023V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident...
V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident macrophages, and its many reported functions and binding partners suggest a complex role in immune function. VSIG4 is reported to have a role in immune surveillance as well as in modulating diverse disease phenotypes such as infections, autoimmune conditions, and cancer. However, the mechanism(s) governing VSIG4's complex, context-dependent role in immune regulation remains elusive. Here, we identify cell surface and soluble glycosaminoglycans, specifically heparan sulfates, as novel binding partners of VSIG4. We demonstrate that genetic deletion of heparan sulfate synthesis enzymes or cleavage of cell-surface heparan sulfates reduced VSIG4 binding to the cell surface. Furthermore, binding studies demonstrate that VSIG4 interacts directly with heparan sulfates, with a preference for highly sulfated moieties and longer glycosaminoglycan chains. To assess the impact on VSIG4 biology, we show that heparan sulfates compete with known VSIG4 binding partners C3b and iC3b. Furthermore, mutagenesis studies indicate that this competition occurs through overlapping binding epitopes for heparan sulfates and complement on VSIG4. Together these data suggest a novel role for heparan sulfates in VSIG4-dependent immune modulation.
Topics: Heparitin Sulfate; Glycosaminoglycans; Receptors, Complement; Cell Membrane; Sulfates
PubMed: 37341346
DOI: 10.1093/glycob/cwad050 -
Biomolecules Oct 2023Human complement receptor 1 (CR1) is a membrane-bound regulator of complement that has been the subject of recent attempts to generate soluble therapeutic compounds... (Review)
Review
Human complement receptor 1 (CR1) is a membrane-bound regulator of complement that has been the subject of recent attempts to generate soluble therapeutic compounds comprising different fragments of its extracellular domain. This review will focus on the extracellular domain of CR1 and detail how its highly duplicated domains work both separately and together to mediate binding to its main ligands C3b and C4b, and to inhibit the classical, lectin, and alternative pathways of the complement cascade via the mechanisms of decay acceleration activity (DAA) and co-factor activity (CFA). Understanding the molecular basis of CR1 activity is made more complicated by the presence not only of multiple ligand binding domains within CR1 but also the fact that C3b and C4b can interact with CR1 as both monomers, dimers, and heterodimers. Evidence for the interaction of CR1 with additional ligands such as C1q will also be reviewed. Finally, we will bring the mechanistic understanding of CR1 activity together to provide an explanation for the differential complement pathway inhibition recently observed with CSL040, a soluble CR1-based therapeutic candidate in pre-clinical development.
Topics: Humans; Complement Activation; Complement System Proteins; Receptors, Complement 3b
PubMed: 37892204
DOI: 10.3390/biom13101522 -
Microbiology Spectrum Nov 2016Myeloid cells make extensive use of the complement system in the context of recruitment, phagocytosis, and other effector functions. There are several types of... (Review)
Review
Myeloid cells make extensive use of the complement system in the context of recruitment, phagocytosis, and other effector functions. There are several types of complement receptors on myeloid cells, including G protein-coupled receptors for localizing the source of complement activation, and three sets of type I transmembrane proteins that link complement to phagocytosis: complement receptor 1, having an extracellular domain with tandem complement regulatory repeats; complement receptors 3 and 4, which are integrin family receptors comprising heterodimers of type I transmembrane subunits; and VSIG4, a member of the Ig superfamily. This review will focus on the role of the different classes of complement receptors and how their activities are integrated in the setting of immune tolerance and inflammatory responses.
Topics: Animals; Cell Adhesion; Humans; Myeloid Cells; Phagocytosis; Receptors, Complement
PubMed: 27809953
DOI: 10.1128/microbiolspec.MCHD-0034-2016 -
Nature Communications Oct 2019Fungal dissemination into the bloodstream is a critical step leading to invasive fungal infections. Here, using intravital imaging, we show that Kupffer cells (KCs) in...
Fungal dissemination into the bloodstream is a critical step leading to invasive fungal infections. Here, using intravital imaging, we show that Kupffer cells (KCs) in the liver have a prominent function in the capture of circulating Cryptococcus neoformans and Candida albicans, thereby reducing fungal dissemination to target organs. Complement C3 but not C5, and complement receptor CRIg but not CR3, are involved in capture of C. neoformans. Internalization of C. neoformans by KCs is subsequently mediated by multiple receptors, including CR3, CRIg, and scavenger receptors, which work synergistically along with C5aR signaling. Following phagocytosis, the growth of C. neoformans is inhibited by KCs in an IFN-γ independent manner. Thus, the liver filters disseminating fungi from circulation via KCs, providing a mechanistic explanation for the enhanced risk of cryptococcosis among individuals with liver diseases, and suggesting a therapeutic strategy to prevent fungal dissemination through enhancing KC functions.
Topics: Animals; Candida albicans; Complement C3; Cryptococcus neoformans; Disease Models, Animal; Female; Humans; Intravital Microscopy; Invasive Fungal Infections; Kupffer Cells; Liver; Male; Mice; Mice, Knockout; Microscopy, Confocal; Phagocytosis; Receptors, Complement
PubMed: 31594939
DOI: 10.1038/s41467-019-12381-5 -
The Journal of Investigative Dermatology Jun 1990Human CR1 is widely distributed in the circulation as a surface receptor as well as in soluble form in the plasma. It mediates a variety of functions that include... (Review)
Review
Human CR1 is widely distributed in the circulation as a surface receptor as well as in soluble form in the plasma. It mediates a variety of functions that include phagocytosis and regulation of the complement cascade. This receptor has been cloned and the primary structure reveals that the cell-bound molecule is an integral membrane protein with typical transmembrane and cytoplasmic domains. Its extracellular portion is composed entirely of 30 short consensus repeats (SCR) each having 60 to 70 amino acids. This type of motif is the common structural element of the superfamily of complement regulatory and receptor proteins on chromosome 1. The amino-terminal 28 SCR of CR1 is uniquely organized into four tandem long homologous repeats (LHR) with sequence homologies among corresponding SCR as high as 99%. Each LHR encodes approximately 45 kD and each except the one that is proximal to the cell surface contains a separate binding site for C3b or C4b. Analysis of the genomic structure of CR1 reveals that these LHR are results of intragenic duplication of 20- to 30-kb segments of DNA. The structural allotypes of CR1 that vary in the lengths of the polypeptides are encoded by alleles that contain different numbers of LHR. Their predicted structures would have different numbers of C3b binding sites, perhaps resulting in molecules with different capacities to bind immune complexes.
Topics: Alleles; Blood Cells; Chemical Phenomena; Chemistry; Humans; Polymorphism, Genetic; Receptors, Complement; Receptors, Complement 3b; Sequence Homology, Nucleic Acid; Structure-Activity Relationship; Transcription, Genetic
PubMed: 2141049
DOI: 10.1111/1523-1747.ep12875150