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Immunity May 2020The cytotoxic activity of myeloid cells is regulated by a balance of signals that are transmitted through inhibitory and activating receptors. The Cluster of... (Review)
Review
The cytotoxic activity of myeloid cells is regulated by a balance of signals that are transmitted through inhibitory and activating receptors. The Cluster of Differentiation 47 (CD47) protein, expressed on both healthy and cancer cells, plays a pivotal role in this balance by delivering a "don't eat me signal" upon binding to the Signal-regulatory protein alpha (SIRPα) receptor on myeloid cells. Here, we review the current understanding of the role of the CD47-SIRPα axis in physiological tissue homeostasis and as a promising therapeutic target in, among others, oncology, fibrotic diseases, atherosclerosis, and stem cell therapies. We discuss gaps in understanding and highlight where additional insight will be beneficial to allow optimal exploitation of this myeloid cell checkpoint as a target in human disease.
Topics: Animals; Antigens, Differentiation; CD47 Antigen; Homeostasis; Humans; Immunotherapy; Myeloid Cells; Neoplasms; Protein Binding; Receptors, Immunologic; Signal Transduction
PubMed: 32433947
DOI: 10.1016/j.immuni.2020.04.011 -
Immunology Apr 2020Interferon-inducible transmembrane (IFITM) proteins are a family of small homologous proteins, localized in the plasma and endolysosomal membranes, which confer cellular... (Review)
Review
Interferon-inducible transmembrane (IFITM) proteins are a family of small homologous proteins, localized in the plasma and endolysosomal membranes, which confer cellular resistance to many viruses. In addition, several distinct functions have been associated with different IFITM family members, including germ cell specification (IFITM1-IFITM3), osteoblast function and bone mineralization (IFITM5) and immune functions (IFITM1-3, IFITM6). IFITM1-3 are expressed by T cells and recent experiments have shown that the IFITM proteins are directly involved in adaptive immunity and that they regulate CD4 T helper cell differentiation in a T-cell-intrinsic manner. Here we review the role of the IFITM proteins in T-cell differentiation and function.
Topics: Adaptive Immunity; Animals; Antigens, Differentiation; Asthma; Cell Differentiation; Cell Membrane; Endosomes; Gene Expression Regulation; Humans; Inflammation; Mice; Protein Isoforms; Signal Transduction; Th1 Cells; Th2 Cells; Virus Diseases; Viruses
PubMed: 31792954
DOI: 10.1111/imm.13163 -
Cells Aug 2021Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as... (Review)
Review
Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as "resting", amoeboid and phagocytic microglia were viewed as "activated". In aged human brains, a fourth, morphologically novel state has been described, i.e., dystrophic microglia, which are thought to be senescent cells. Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances, they seem to have an "expiration date" limiting their capacity to phagocytose and support neurons. Identifying factors that drive microglial aging may thus be helpful to delay the onset of neurodegenerative diseases, such as Alzheimer's disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations. Given the heterogeneity of pathologic states in the central nervous system, the need for accurately describing microglial morphology and expression patterns becomes increasingly important. Here, we review commonly used microglial markers and their fluctuations in expression in health and disease, with a focus on IBA1 low/negative microglia, which can be found in individuals with liver disease.
Topics: Animals; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Antigens, Differentiation, Myelomonocytic; Brain; Calcium-Binding Proteins; Histocompatibility Antigens Class II; Humans; Membrane Proteins; Microfilament Proteins; Microglia; Nerve Tissue Proteins; Neurodegenerative Diseases; Phagocytes; Phenotype; Receptors, Purinergic P2Y12; Signal Transduction
PubMed: 34571885
DOI: 10.3390/cells10092236 -
Cells May 2020Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors... (Review)
Review
Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors including CD163 and CD206, which are upregulated in response to inflammation. In healthy individuals, soluble forms of CD163 and CD206 are constitutively shed from macrophages, however, during inflammation pathogen- and damage-associated stimuli induce this shedding. Activation of resident liver macrophages viz. Kupffer cells is part of the inflammatory cascade occurring in acute and chronic liver diseases. We here review the existing literature on sCD163 and sCD206 function and shedding, and potential as biomarkers in acute and chronic liver diseases with a particular focus on Acute-on-Chronic Liver Failure (ACLF). In multiple studies sCD163 and sCD206 are elevated in relation to liver disease severity and established as reliable predictors of morbidity and mortality. However, differences in expression- and shedding-stimuli for CD163 and CD206 may explain dissimilarities in prognostic utility in patients with acute decompensation of cirrhosis and ACLF.
Topics: Acute-On-Chronic Liver Failure; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Humans; Lectins, C-Type; Macrophage Activation; Macrophages; Mannose Receptor; Mannose-Binding Lectins; Receptors, Cell Surface
PubMed: 32397365
DOI: 10.3390/cells9051175 -
Immunity Mar 2022Dual blockade of the PD-1 and TIGIT coinhibitory receptors on T cells shows promising early results in cancer patients. Here, we studied the mechanisms whereby PD-1...
Dual blockade of the PD-1 and TIGIT coinhibitory receptors on T cells shows promising early results in cancer patients. Here, we studied the mechanisms whereby PD-1 and/or TIGIT blockade modulate anti-tumor CD8 T cells. Although PD-1 and TIGIT are thought to regulate different costimulatory receptors (CD28 and CD226), effectiveness of PD-1 or TIGIT inhibition in preclinical tumor models was reduced in the absence of CD226. CD226 expression associated with clinical benefit in patients with non-small cell lung carcinoma (NSCLC) treated with anti-PD-L1 antibody atezolizumab. CD226 and CD28 were co-expressed on NSCLC infiltrating CD8 T cells poised for expansion. Mechanistically, PD-1 inhibited phosphorylation of both CD226 and CD28 via its ITIM-containing intracellular domain (ICD); TIGIT's ICD was dispensable, with TIGIT restricting CD226 co-stimulation by blocking interaction with their common ligand PVR (CD155). Thus, full restoration of CD226 signaling, and optimal anti-tumor CD8 T cell responses, requires blockade of TIGIT and PD-1, providing a mechanistic rationale for combinatorial targeting in the clinic.
Topics: Antigens, Differentiation, T-Lymphocyte; CD28 Antigens; CD8-Positive T-Lymphocytes; Humans; Neoplasms; Programmed Cell Death 1 Receptor; Receptors, Immunologic
PubMed: 35263569
DOI: 10.1016/j.immuni.2022.02.005 -
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 -
International Journal of Biological... 2021The adaptive immune checkpoints such as PD-1(programmed death-1)/PD-L1 (programmed death-ligand 1) play an important role in cancer immunotherapy, whereas increasing... (Review)
Review
The adaptive immune checkpoints such as PD-1(programmed death-1)/PD-L1 (programmed death-ligand 1) play an important role in cancer immunotherapy, whereas increasing evidence suggests that cancer cell evades immune surveillance by innate immune checkpoints such as SIRPα (signal-regulatory protein α)/CD47 (cluster of differentiation 47). In multiple types of cancer cells and solid tumor tissues, highly expressed CD47 protein level has been observed, which is triggered by some transcription factors including NFκB, Myc, and HIF. As a transmembrane protein, the binding of CD47 to SIRPα ligand on phagocytes results in phagocytosis resistance and cancer cell immune escape. In contrast, CD47-SIRPα interaction blockade enhances cancer cell clearance by phagocytes such as macrophages and dendritic cells (DCs) to activate an innate immune response, whereas this process could promote antigen cross-presentation by antigen present cells (APCs) leading to T cell priming, consequently, activates an adaptive antitumor immune response. In this review, we discussed the current SIRPα-CD47 axis-mediated cancer cell immune escape and immunotherapy, which could provide an effective antitumor strategy by the innate and adaptive immune response.
Topics: Animals; Antigens, Differentiation; CD47 Antigen; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Phagocytosis; Receptors, Immunologic; Tumor Escape
PubMed: 34512146
DOI: 10.7150/ijbs.60782 -
International Journal of Molecular... Jul 2020The macrophage is a key cell in the pro- and anti-inflammatory response including that of the inflammatory microenvironment of malignant tumors. Much current drug... (Review)
Review
The macrophage is a key cell in the pro- and anti-inflammatory response including that of the inflammatory microenvironment of malignant tumors. Much current drug development in chronic inflammatory diseases and cancer therefore focuses on the macrophage as a target for immunotherapy. However, this strategy is complicated by the pleiotropic phenotype of the macrophage that is highly responsive to its microenvironment. The plasticity leads to numerous types of macrophages with rather different and, to some extent, opposing functionalities, as evident by the existence of macrophages with either stimulating or down-regulating effect on inflammation and tumor growth. The phenotypes are characterized by different surface markers and the present review describes recent progress in drug-targeting of the surface marker CD163 expressed in a subpopulation of macrophages. CD163 is an abundant endocytic receptor for multiple ligands, quantitatively important being the haptoglobin-hemoglobin complex. The microenvironment of inflammation and tumorigenesis is particular rich in CD163 macrophages. The use of antibodies for directing anti-inflammatory (e.g., glucocorticoids) or tumoricidal (e.g., doxorubicin) drugs to CD163 macrophages in animal models of inflammation and cancer has demonstrated a high efficacy of the conjugate drugs. This macrophage-targeting approach has a low toxicity profile that may highly improve the therapeutic window of many current drugs and drug candidates.
Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Humans; Inflammation; Macrophages; Molecular Targeted Therapy; Neoplasms; Receptors, Cell Surface; Tumor Microenvironment
PubMed: 32752088
DOI: 10.3390/ijms21155497 -
Frontiers in Immunology 2020CD47 is an immunoglobulin that is overexpressed on the surface of many types of cancer cells. CD47 forms a signaling complex with signal-regulatory protein α (SIRPα),... (Review)
Review
CD47 is an immunoglobulin that is overexpressed on the surface of many types of cancer cells. CD47 forms a signaling complex with signal-regulatory protein α (SIRPα), enabling the escape of these cancer cells from macrophage-mediated phagocytosis. In recent years, CD47 has been shown to be highly expressed by various types of solid tumors and to be associated with poor patient prognosis in various types of cancer. A growing number of studies have since demonstrated that inhibiting the CD47-SIRPα signaling pathway promotes the adaptive immune response and enhances the phagocytosis of tumor cells by macrophages. Improved understanding in this field of research could lead to the development of novel and effective anti-tumor treatments that act through the inhibition of CD47 signaling in cancer cells. In this review, we describe the structure and function of CD47, provide an overview of studies that have aimed to inhibit CD47-dependent avoidance of macrophage-mediated phagocytosis by tumor cells, and assess the potential and challenges for targeting the CD47-SIRPα signaling pathway in anti-cancer therapy.
Topics: Adaptive Immunity; Animals; Antibodies, Monoclonal, Humanized; Antigens, Differentiation; Antineoplastic Agents, Immunological; CD47 Antigen; Humans; Immunotherapy; Macrophages; Neoplasms; Phagocytosis; Receptors, Immunologic; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 32082311
DOI: 10.3389/fimmu.2020.00018 -
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