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Journal For Immunotherapy of Cancer Jul 2022Myeloid immune cells are frequently present in the tumor environment, and although they can positively contribute to tumor control they often negatively impact... (Review)
Review
Myeloid immune cells are frequently present in the tumor environment, and although they can positively contribute to tumor control they often negatively impact anticancer immune responses. One way of inhibiting the positive contributions of myeloid cells is by signaling through the cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) axis. The SIRPα receptor is expressed on myeloid cells and is an inhibitory immune receptor that, upon binding to CD47 protein, delivers a 'don't eat me' signal. As CD47 is often overexpressed on cancer cells, treatments targeting CD47/SIRPα have been under active investigation and are currently being tested in clinical settings. Interestingly, the CD47/SIRPα axis is also involved in T cell-mediated antitumor responses. In this perspective we provide an overview of recent studies showing how therapeutic blockade of the CD47/SIRPα axis improves the adaptive immune response. Furthermore, we discuss the interconnection between the myeloid CD47/SIRPα axis and adaptive T cell responses as well as the potential therapeutic role of the CD47/SIRPα axis in tumors with acquired resistance to the classic immunotherapy through major histocompatibility complex downregulation. Altogether this review provides a profound insight for the optimal exploitation of CD47/SIRPα immune checkpoint therapy.
Topics: Adaptive Immunity; Antigens, Differentiation; CD47 Antigen; Humans; Neoplasms; Phagocytosis
PubMed: 35831032
DOI: 10.1136/jitc-2022-004589 -
Antioxidants & Redox Signaling Jun 2013The hemoglobin (Hb) scavenger receptor, CD163, is a macrophage-specific protein and the upregulated expression of this receptor is one of the major changes in the... (Review)
Review
SIGNIFICANCE
The hemoglobin (Hb) scavenger receptor, CD163, is a macrophage-specific protein and the upregulated expression of this receptor is one of the major changes in the macrophage switch to alternative activated phenotypes in inflammation. Accordingly, a high CD163 expression in macrophages is a characteristic of tissues responding to inflammation. The scavenging of the oxidative and proinflammatory Hb leading to stimulation of the heme-oxygenase-1 and production of anti-inflammatory heme metabolites indicates that CD163 thereby indirectly contributes to the anti-inflammatory response.
RECENT ADVANCES
In addition to this biological role in inflammation, CD163 is a potential inflammation biomarker and a therapeutic target. The biomarker form of CD163 is the soluble plasma CD163 that arises from the increased shedding of CD163 mediated by the tumor necrosis factor-α (TNF-α) cleaving enzyme. This explains that a steadily increasing literature documents that the plasma level of soluble CD163 is increased in a large spectrum of acute and chronic inflammatory disorders. The nonshed membrane form of CD163 in macrophages constitutes a target for drugs to be directed to macrophages in inflammation. This approach has been used in an animal inflammation model to highly increase the apparent therapeutic index of anti-inflammatory glucocorticoid drug that was coupled to an anti-CD163 antibody. Furthermore, other recent animal data, which indirectly involve CD163 in macrophages, demonstrate that injections of haptoglobin attenuate Hb-induced damages after blood transfusion.
CRITICAL ISSUES AND FUTURE DIRECTIONS
The diagnostic and therapeutic properties of CD163 await further clinical studies and regulatory approval before implementation in the clinic.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Gene Expression Regulation; Haptoglobins; Hemoglobins; Humans; Inflammation; Macrophages; Receptors, Cell Surface
PubMed: 22900885
DOI: 10.1089/ars.2012.4834 -
The Journal of Biological Chemistry Jan 2023Interferon-induced transmembrane proteins (IFITMs) are broad spectrum antiviral factors that inhibit the entry of a wide range of clinically important pathogens... (Review)
Review
Interferon-induced transmembrane proteins (IFITMs) are broad spectrum antiviral factors that inhibit the entry of a wide range of clinically important pathogens including influenza A virus, HIV-1, and Dengue virus. IFITMs are thought to act primarily by antagonizing virus-cell membrane fusion in this regard. However, recent work on these proteins has uncovered novel post-entry viral restriction mechanisms. IFITMs are also increasingly thought to have a role regulating immune responses, including innate antiviral and inflammatory responses as well as adaptive T-cell and B-cell responses. Further, IFITMs may have pathological activities in cancer, wherein IFITM expression can be a marker of therapeutically resistant and aggressive disease courses. In this review, we summarize the respective literatures concerning these apparently diverse functions with a view to identifying common themes and potentially yielding a more unified understanding of IFITM biology.
Topics: Humans; Membrane Proteins; Virus Internalization; Antiviral Agents; Virus Diseases; Neoplasms; Antigens, Differentiation
PubMed: 36435199
DOI: 10.1016/j.jbc.2022.102741 -
Genes Jan 2021Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (). Originally described as a component of the cornified... (Review)
Review
Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (). Originally described as a component of the cornified envelope, the function of stratified epithelia-expressed is unknown. Both the lack of knowledge about the gene role under physiological conditions and the emerging link of to various human diseases, including cancer, attract research interest. The association of expression with poor prognosis of patients suffering from oesophageal carcinoma, glioblastoma multiforme, and myelodysplastic syndromes suggests that may play a role in human tumourigenesis. Three isoforms code for the secreted proteins with putative function as signalling molecules, yet with poorly described effects. In this first review about , we summarised the current knowledge accumulated since its original description, and we discuss the potential mechanisms and roles of in both physiology and pathology.
Topics: Antigens, Differentiation; Carcinogenesis; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Neoplasms
PubMed: 33477529
DOI: 10.3390/genes12010108 -
Science (New York, N.Y.) Jul 2013CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPα, the receptor...
CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPα variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This "one-two punch" directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.
Topics: Adjuvants, Immunologic; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antigens, Differentiation; CD47 Antigen; Cell Line, Tumor; Directed Molecular Evolution; Humans; Immunotherapy; Macrophage Activation; Mice; Neoplasms; Phagocytosis; Receptors, Immunologic; Rituximab
PubMed: 23722425
DOI: 10.1126/science.1238856 -
Signal Transduction and Targeted Therapy Oct 2020
Review
Topics: Animals; Antigens, Differentiation; Humans; Membrane Glycoproteins; Receptors, Immunologic; Tumor-Associated Macrophages
PubMed: 33037186
DOI: 10.1038/s41392-020-00356-8 -
Molecular Medicine Reports May 2017Macrophages exert important functions in the balance and efficiency of immune responses, and participate in innate and adaptive immunity. The proinflammatory actions of... (Review)
Review
Macrophages exert important functions in the balance and efficiency of immune responses, and participate in innate and adaptive immunity. The proinflammatory actions of macrophages are implicated in autoimmune diseases. Unlike classically activated M1 macrophages, the alternatively activated cluster of differentiation (CD)163+ and CD206+ M2 macrophages are involved in tissue repair and wound healing, and use oxidative metabolism to support their long‑term functions. CD163 is a member of the scavenger receptor superfamily, categorized into class B, and its soluble(s) form, sCD163, is a marker of activated M2 macrophages. CD163 is selectively expressed in cells of the monocyte and macrophage lineages; however, its biological role has yet to be elucidated. The expression of sCD163 is markedly induced by anti‑inflammatory mediators, such as glucocorticoids and interleukin‑10, whereas it is inhibited by proinflammatory mediators, such as interferon‑γ. These findings suggest that CD163 may serve as a potential target for the therapeutic modulation of inflammatory responses. The concentration of sCD163 in blood is associated with acute and chronic inflammatory processes in autoimmune disorders of connective tissue, fat metabolism and cardiovascular diseases, and it can be used for the assessment of cancer prognosis. A role for sCD163 in the pathogenesis of asthma has also been proposed. The present review serves to present the available knowledge concerning the implication of sCD163 in the pathophysiological mechanisms of asthma, and evaluate its potential as a biomarker and possible therapeutic target for asthma.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Asthma; Biomarkers; Cytokine TWEAK; Haptoglobins; Humans; Interleukin-6; Macrophages; Oxidative Stress; Receptors, Cell Surface
PubMed: 28350095
DOI: 10.3892/mmr.2017.6393 -
Frontiers in Immunology 2018Following T cell receptor triggering, T cell activation is initiated and amplified by the assembly at the TCR/CD3 macrocomplex of a multitude of stimulatory enzymes that... (Review)
Review
Following T cell receptor triggering, T cell activation is initiated and amplified by the assembly at the TCR/CD3 macrocomplex of a multitude of stimulatory enzymes that activate several signaling cascades. The potency of signaling is, however, modulated by various inhibitory components already at the onset of activation, long before co-inhibitory immune checkpoints are expressed to help terminating the response. CD5 and CD6 are surface glycoproteins of T cells that have determinant roles in thymocyte development, T cell activation and immune responses. They belong to the superfamily of scavenger receptor cysteine-rich (SRCR) glycoproteins but whereas the inhibitory role of CD5 has been established for long, there is still controversy on whether CD6 may have similar or antagonistic functions on T cell signaling. Analysis of the structure and molecular associations of CD5 and CD6 indicates that these molecules assemble at the cytoplasmic tail a considerable number of signaling effectors that can putatively transduce diverse types of intracellular signals. Biochemical studies have concluded that both receptors can antagonize the flow of TCR-mediated signaling; however, the impact that CD5 and CD6 have on T cell development and T cell-mediated immune responses may be different. Here we analyze the signaling function of CD6, the common and also the different properties it exhibits comparing with CD5, and interpret the functional effects displayed by CD6 in recent animal models.
Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; CD5 Antigens; Humans; Lymphocyte Activation; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocytes
PubMed: 30619347
DOI: 10.3389/fimmu.2018.02994 -
Journal of Leukocyte Biology Mar 2000Ecto-enzymes are catalytic membrane proteins with their active sites outside the cell. They include cholinesterase, which inactivates acetylcholine, and... (Review)
Review
Ecto-enzymes are catalytic membrane proteins with their active sites outside the cell. They include cholinesterase, which inactivates acetylcholine, and angiotensin-converting enzyme, which converts angiotensin I to biologically active angiotensin II, and numerous other peptidases, transpeptidases, nucleotidases, phosphodiesterases, and phosphatases. Many CD antigens of leukocytes are ecto-enzymes; some CD antigens for which no function is currently known are probably ecto-enzymes. Expression is highly regulated and correlated with differentiation and activation. Some are highly restricted in distribution; others are ubiquitous. Many are shared between leukocytes and non-hematogenous cells. Biological functions appear to depend on the type and location of the cell in which expression occurs, and include recycling of nutrients, local control of response to cytokines and hormones, bone formation, cell mobility, invasion, and metastasis. Many novel regulatory functions of ecto-enzymes remain to be discovered, and may reveal new mechanisms of local extracellular control of cellular function.
Topics: Amino Acid Sequence; Animals; Antigens, Differentiation; Cell Membrane; Humans; Hydrolases; Molecular Sequence Data; Nucleosides; Nucleotides; Receptors, Cell Surface; Substrate Specificity; Transferases
PubMed: 10733089
DOI: 10.1002/jlb.67.3.285 -
The Biochemical Journal Sep 1996CD28 and the related molecule cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), together with their natural ligands B7.1 and B7.2, have been implicated in the... (Review)
Review
CD28 and the related molecule cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), together with their natural ligands B7.1 and B7.2, have been implicated in the differential regulation of several immune responses. CD28 provides signals during T cell activation which are required for the production of interleukin 2 and other cytokines and chemokines, and it has also been implicated in the regulation of T cell anergy and programmed T cell death. The biochemical signals provided by CD28 are cyclosporin A-resistant and complement those provided by the T cell antigen receptor to allow full activation of T cells. Multiple signalling cascades which may be independent of, or dependent on, protein tyrosine kinase activation have been demonstrated to be activated by CD28, including activation of phospholipase C, p21ran, phosphoinositide 3-kinase, sphingomyelinase/ceramide and 5-lipoxygenase. The relative contributions of these cascades to overall CD28 signalling are still unknown, but probably depend on the state of activation of the T cell and the level of CD28 activation. The importance of these signalling cascades (in particular the phosphoinositide 3-kinase-mediated cascade) to functional indications of CD28 activation, such as interleukin 2 gene regulation, has been investigated using pharmacological and genetic manipulations. These approaches have demonstrated that CD28-activated signalling cascades regulate several transcription factors involved in interleukin 2 transcriptional activation. This review describes in detail the structure and expression of the CD28 and B7 families, the functional outcomes of CD28 ligation and the signalling events that are thought to mediate these functions.
Topics: Abatacept; Amino Acid Sequence; Animals; Antigens, CD; Antigens, Differentiation; Apoptosis; Binding Sites; CD28 Antigens; CTLA-4 Antigen; Chromosome Mapping; Chromosomes, Human, Pair 2; Clonal Anergy; Consensus Sequence; Humans; Immunoconjugates; Lymphocyte Activation; Models, Immunological; Models, Molecular; Phosphatidylinositol 3-Kinases; Phosphotransferases (Alcohol Group Acceptor); Protein-Tyrosine Kinases; Signal Transduction; T-Lymphocytes
PubMed: 8809021
DOI: 10.1042/bj3180361