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Cell surface CD47 interacts with its receptor, signal-regulatory-protein α (SIRPα) that is expressed predominantly on macrophages, to inhibit phagocytosis of normal, healthy cells. This "don't eat me" signal is mediated through tyrosine phosphorylation of SIRPα at the cytoplasmic ITIM motifs and the recruitment of the phosphatase, SHP-1. We previously revealed a novel mechanism for the activation of the STAT3 pathway and the regulation of human APC maturation and function that is based on cell:cell interaction. In this study, we present evidence supporting the notion that CD47:SIRPα serves as a cell surface receptor: ligand pair involved in this contact-dependent STAT3 activation and regulation of APC maturation. We show that upon co-culturing APC with various primary and tumor cell lines STAT3 phosphorylation and IL-10 expression are induced, and such regulation could be suppressed by specific CD47 siRNAs and shRNAs. Significantly, >50% reduction in CD47 expression abolished the contact-dependent inhibition of T cell activation. Furthermore, co-immunoprecipitation experiments revealed a physical association between SIRPα and STAT3. Thus, we suggest that in addition to signaling through the ITIM-SHP-1 complex that transmit an anti-phagocytotic, CD47:SIRPα also triggers STAT3 signaling that is linked to an immature APC phenotype and peripheral tolerance under steady state and pathological conditions.
Glypican-3 (GPC3) is a well-characterized hepatocellular carcinoma (HCC)-associated antigen, yet anti-GPC3 therapies have achieved only minimal clinical progress. CD47 is a ubiquitously expressed innate immune checkpoint that promotes evasion of tumors from immune surveillance. Given both the specific expression of GPC3 in HCC and the known phagocytosis inhibitory effect of CD47 in liver cancer, we hypothesized that a bispecific antibody (BsAb) that co-engages with GPC3 and CD47 may offer excellent antitumor efficacy with minimal toxicity. Here, we generated a novel BsAb: GPC3/CD47 biAb. With the use of both in vitro and in vivo assays, we found that GPC3/CD47 biAb exerts strong antitumor activity preferentially against dual antigen-expressing tumor cells. In hCD47/human signal regulatory protein alpha (hCD47/hSIRPα) humanized mice, GPC3/CD47 biAb had an extended serum half-life without causing systemic toxicity. Importantly, GPC3/CD47 biAb induced enhanced Fc-mediated effector functions to dual antigen-expressing HCC cells in vitro, and both macrophages and neutrophils are required for its strong efficacy against xenograft HCC tumors. Notably, GPC3/CD47 biAb outperformed monotherapies and a combination therapy with anti-CD47 and anti-GPC3 monoclonal antibodies (mAbs) in a xenograft HCC model. Our study illustrates a strategy for improving HCC treatment by boosting innate immune responses and presents new insights to inform antibody design for the future development of innovative immune therapies.
Malaria symptoms and pathology are initiated by invasion of host erythrocytes by Plasmodium merozoites in a complex process that involves interactions between parasite and host erythrocyte proteins. Erythrocyte invasion presents attractive targets for malaria vaccine and drug development. Recently it was observed that antibodies against PfMSA180 (PF3D7_1014100) are associated with protection from symptomatic malaria, suggesting that this protein is a target of naturally acquired protective antibodies. Here we characterize PfMSA180, a ~170 kDa merozoite surface antigen that is potentially involved in erythrocyte invasion. PfMSA180 synthesized by the wheat germ cell-free system was used to raise antibodies in rabbits. Growth inhibition assays revealed that parasite invasion is inhibited by antibodies to the PfMSA180 C-terminal region, which contains an erythrocyte-binding domain. Surface plasmon resonance analysis showed that PfMSA180 specifically interacts with human erythrocyte integrin associated protein (CD47), suggesting that PfMSA180 plays a role during merozoite invasion of erythrocytes. Polymorphism analysis revealed that pfmsa180 is highly conserved among field isolates. We show that naturally acquired PfMSA180-specific antibodies responses are associated with protective immunity in a malaria-exposed Thai population. In sum, the data presented here supports further evaluation of the conserved erythrocyte-binding C-terminal region of PfMSA180 as an asexual blood-stage malaria vaccine candidate.
Antigen-presenting cells (APCs) are powerful tools to expand antigen-specific T cells ex vivo and in vivo for tumor immunotherapy, but suffer from time-consuming generation and biosafety concerns raised by live cells. Alternatively, the cell-free artificial antigen-presenting cells (aAPCs) have been rapidly developed. Nanoscale aAPCs are recently proposed owing to their superior biodistribution and reduced embolism than conventional cell-sized aAPCs, but pose the challenges: easier cellular uptake and smaller contact surface area with T cells than the cell-sized counterparts. This study aimed to fabricate a new "stealth" nano-aAPCs with microscale contact surface area to minimize cellular uptake and activate antigen-specific T cells by combination uses of ellipsoidal stretch, PEGylation, and self-marker CD47-Fc conjugation.
Cancer cells overexpress CD47 to subvert phagocytic elimination and evade immunogenic processing of cancer antigens. Moreover, CD47 overexpression inhibits the antibody-dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC) activities of therapeutic anticancer antibodies. Consequently, CD47-blocking antibodies have been developed to overcome the immunoevasive activities of cancer cell-expressed CD47. However, the wide-spread expression of CD47 on normal cells forms a massive "antigen sink" that potentially limits sufficient tumor accretion of these antibodies. Additionally, a generalized blockade of CD47-SIRPα interaction may ultimately lead to unintended cross-presentation of self-antigens potentially promoting autoimmunity. To address these issues, we constructed a bispecific antibody, designated bsAb CD47xEGFR-IgG1, that blocks cancer cell surface-expressed CD47 in an EGFR-directed manner. BsAb CD47xEGFR-IgG1 selectively induced phagocytic removal of EGFRpos/CD47pos cancer cells and endowed neutrophils with capacity to kill these cancer cells by trogoptosis; an alternate form of ADCC that disrupts the target cell membrane. Importantly, bsAb CD47xEGFR-IgG1 selectively enhanced phagocytosis and immunogenic processing of EGFRpos/CD47pos cancers cells ectopically expressing viral protein CMVpp65. In conclusion, bsAb CD47xEGFR-IgG1 may be useful to reduce on-target/off-tumor effects of CD47-blocking approaches, enhance cancer cell elimination by trogoptosis, and promote adaptive anticancer immune responses.
Rationale: Many cancers have evolved different mechanisms to evade immune surveillance. Macrophages, the innate defense of the immune system, are limited in their phagocytosis by CD47 anti-phagocytic signaling expressed on the surface of tumor cells. Although the CD47 monoclonal antibody (aCD47) strategy has been extensively studied in clinical trials, the depletion of aCD47 by red blood cells (RBCs) and the resulting hematotoxicity have impeded their application in tumor treatment. Methods: Here, we reported an injectable hydrogel scaffold that allowed for local delivery of small-molecule inhibitor PQ912. The biodegradable hydrogel scaffold (PQ/PB-Gel) was formed by rapid cross-linking of tetra-armed PEG succinimidyl succinate (Tetra-PEG-SS) solution and alkalescent bovine serum albumin (BSA) solution through ammonolysis reaction. Results: PQ/PB-Gel had excellent effect on inhibiting local recurrence of two kinds of tumors. The hydrogel system inhibited the generation of "don't eat me" signals during the treatment cycle by inhibiting the expression of newly generated neoplastic CD47. Thus, it avoided adverse reactions such as erythrocytopenia after the use of aCD47 in terms of safety. After the "don't eat me" signal was blocked the clearance and recognition of cancer cells by macrophages and antigen-presenting cells were enhanced, sequentially systemic immune response was activated and further memory T lymphocyte (T cell) formation was induced. Conclusions: PQ/PB-Gel had a simple preparation and administration method, low production cost, excellent efficacy and low toxicity, so it had good practicability. This might provide a safe alternative strategy for aCD47 for inhibit local tumor recurrence and distal metastasis in postoperative immunotherapy.
Extensive clinical and experimental evidence suggests that macrophages play a crucial role in cancer immunotherapy. Cluster of differentiation (CD) 47, which is found on both healthy and malignant cells, regulates macrophage-mediated phagocytosis by sending a "don't eat me" signal to the signal regulatory protein alpha (SIRPα) receptor. Increasing evidence demonstrates that blocking CD47 interaction with SIRPα can enhance cancer cell clearance by macrophages. Additionally, inhibition of CD47/SIRPα interaction can increase antigen cross-presentation, leading to T-cell priming and an activated adaptive antitumor immune response. Therefore, inhibiting CD47/SIRPα axis has a significant impact on tumor immunotherapy. Studies on CD47 monoclonal antibodies are at the forefront of research, and impressive results have been obtained. Nevertheless, hematotoxicity, especially anemia, has become the most common adverse effect of the CD47 monoclonal antibody. More specific targeted drugs (i.e., bispecific antibodies, SIRPα/Fc fusion protein antibodies, and small-molecule inhibitors) have been developed to reduce hematotoxicity. Here, we review the present usage of CD47 antagonists for the treatment of lymphomas and hematologic neoplasms from the perspectives of structure, function, and clinical trials, including a comprehensive overview of the drugs in development.
Osteosarcoma is the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease still have a poor prognosis, illustrating the need for alternative therapies. In this study, we explored the use of antibodies that block CD47 with a tumor growth suppressive effect on osteosarcoma. We first found that up-regulation of CD47 mRNA levels in the tumorous tissues from eight patients with osteosarcoma when compared with that in adjacent non-tumorous tissues. Further western-blot (WB) and immunohistochemistry (IHC) demonstrated that CD47 protein level was highly expressed in osteosarcoma compared to normal osteoblastic cells and adjacent non-tumorous tissues. Osteosarcoma cancer stem cell markers staining shown that the majority of CD44+ cells expressed CD47 albeit with different percentages (ranging from 80% to 99%). Furthermore, high CD47 mRNA expression levels were associated with a decreased probability of progression-free and overall survival. In addition, blockade of CD47 by specific Abs suppresses the invasive ability of osteosarcoma tumor cells and further inhibits spontaneous pulmonary metastasis of KRIB osteosarcoma cells in vivo. Finally, CD47 blockade increases macrophage phagocytosis of osteosarcoma tumor cells.In conclusion, our findings demonstrate that CD47 is a critical regulator in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by anti-CD47 may be a novel immunotherapeutic approach in the management of this tumor.
It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 "don't eat me" signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions. A CD47 mimic that acts as an essential virulence factor is encoded by all poxviruses, but CD47 expression on infected cells was found to be upregulated even by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that encode no mimic. CD47 upregulation was revealed to be a host response induced by the stimulation of both endosomal and cytosolic pathogen recognition receptors (PRRs). Furthermore, proinflammatory cytokines, including those found in the plasma of hepatitis C patients, upregulated CD47 on uninfected dendritic cells, thereby linking innate modulation with downstream adaptive immune responses. Indeed, results from antibody-mediated CD47 blockade experiments as well as CD47 knockout mice revealed an immunosuppressive role for CD47 during infections with lymphocytic choriomeningitis virus and Mycobacterium tuberculosis Since CD47 blockade operates at the level of pattern recognition receptors rather than at a pathogen or antigen-specific level, these findings identify CD47 as a novel potential immunotherapeutic target for the enhancement of immune responses to a broad range of infectious agents.IMPORTANCE Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile.
CD47 serves as an anti-phagocytic receptor that is upregulated by cancer to promote immune escape. As such, CD47 is the focus of intense immuno-oncology drug development efforts. However, as CD47 is expressed ubiquitously, clinical development of conventional drugs, e.g., monoclonal antibodies, is confronted with patient safety issues and poor pharmacology due to the widespread CD47 "antigen sink". A potential solution is tumor-directed blockade of CD47, which can be achieved with bispecific antibodies (biAbs). Using mouse CD47-blocking biAbs in a syngeneic tumor model allowed us to evaluate the efficacy of tumor-directed blockade of CD47 in the presence of the CD47 antigen sink and a functional adaptive immune system. We show here that CD47-targeting biAbs inhibited tumor growth in vivo, promoting durable antitumor responses and stimulating CD8+ T cell activation in vitro. In vivo efficacy of the biAbs could be further enhanced when combined with chemotherapy or PD-1/PD-L1 immune checkpoint blockade. We also show that selectivity and pharmacological properties of the biAb are dependent on the affinity of the anti-CD47 arm. Taken together, our study validates the approach to use CD47-blocking biAbs either as a monotherapy or part of a multi-drug approach to enhance antitumor immunity.
Senescence is a tumor-suppressive mechanism induced by telomere shortening, oncogenes, or chemotherapy treatment. Although it is clear that this suppressive pathway leads to a permanent arrest in primary cells, this might not be the case in cancer cells that have inactivated their suppressive pathways. We have recently shown that subpopulations of cells can escape chemotherapy-mediated senescence and emerge as more transformed cells that induce tumor formation, resist anoikis, and are more invasive. In this study, we characterized this emergence and showed that senescent cells favor tumor growth and metastasis, in vitro and in vivo. Senescence escape was regulated by secreted proteins produced during emergence. Among these, we identified thrombospondin-1 (TSP1), a protein produced by senescent cells that prevented senescence escape. Using SWATH quantitative proteomic analysis, we found that TSP1 can be detected in the serum of patients suffering from triple-negative breast cancer and that its low expression was associated with treatment failure. The results also indicate that senescence escape is explained by the emergence of CD47low cells that express a reduced level of CD47, the TSP1 receptor. The results show that CD47 expression is regulated by p21waf1. The cell cycle inhibitor was sufficient to maintain senescence since its downregulation in senescent cells increased cell emergence. This leads to the upregulation of Myc, which then binds to the CD47 promoter to repress its expression, allowing the generation of CD47low cells that escape the suppressive arrest. Altogether, these results uncovered a new function for TSP1 and CD47 in the control of chemotherapy-mediated senescence.
Chimeric antigen receptor (CAR) T cells have revolutionized blood cancer immunotherapy; however, their efficacy against solid tumors has been limited. A common mechanism of tumor escape from single target therapies is downregulation or mutational loss of the nominal epitope. Targeting multiple antigens may thus improve the effectiveness of CAR immunotherapies. We generated dual CAR-T cells targeting two tumor antigens: TAG-72 (tumor-associated glycoprotein 72) and CD47. TAG-72 is a pan-adenocarcinoma oncofetal antigen, highly expressed in ovarian cancers, with increased expression linked to disease progression. CD47 is ubiquitously overexpressed in multiple tumor types, including ovarian cancer; it is a macrophage "don't eat me" signal. However, CD47 is also expressed on many normal cells. To avoid this component of the dual CAR-T cells killing healthy tissue, we designed a truncated CD47 CAR devoid of intracellular signaling domains. The CD47 CAR facilitates binding to CD47+ cells, increasing the prospect of TAG-72+ cell elimination via the TAG-72 CAR. Furthermore, we could reduce the damage to normal tissue by monomerizing the CD47 CAR. Our results indicate that the co-expression of the TAG-72 CAR and the CD47-truncated monomer CAR on T cells could be an effective, dual CAR-T cell strategy for ovarian cancer, also applicable to other adenocarcinomas.
The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic application of CAR-Ms in ovarian cancer.
Chimeric antigen receptor (CAR) T cell therapy has been successfully applied in treating lymphoma malignancies, but not in solid tumors. CD47 is highly expressed on tumor cells and its overexpression is believed to inhibit phagocytosis by macrophages and dendritic cells. Given the antitumor activity against preclinical model of CD47-blocking to induce the innate and adaptive immune system in the tumor microenvironment, here we developed a CAR-T cell secreting CD47 blocker signal regulatory protein α (SIRPα)-Fc fusion protein (Sirf CAR-T) to boost CAR-T cell therapeutic effect in solid tumor therapy.
CD47 is a glycoprotein of the immunoglobulin superfamily that is often overexpressed in different types of hematological and solid cancer tumors and plays important role in blocking phagocytosis, increased tumor survival, metastasis and angiogenesis. In the present report, we designed CAR (chimeric antigen receptor)-T cells that bind CD47 antigen. We used ScFv (single chain variable fragment) from mouse CD47 antibody to generate CD47-CAR-T cells for targeting different cancer cell lines. CD47-CAR-T cells effectively killed ovarian, pancreatic and other cancer cells and produced high level of cytokines that correlated with expression of CD47 antigen. In addition, CD47-CAR-T cells significantly blocked BxPC3 pancreatic xenograft tumor growth after intratumoral injection into NSG mice. Moreover, we humanized mouse CD47 ScFv and showed that it effectively bound CD47 antigen. The humanized CD47-CAR-T cells also specifically killed ovarian, pancreatic, and cervical cancer cell lines and produced IL-2 that correlated with expression of CD47. Thus, CD47-CAR-T cells can be used as a novel cellular therapeutic agent for treating different types of cancer.
Phagocytosis of cancer cells by antigen presenting cells (APCs) is critical to activate the host's immune responses. However, the targeting ability of APCs to cancer cells is limited by the upregulation of transmembrane protein CD47 on the cancer cell surface. Blocking CD47 can affect the macrophage-mediated phagocytosis. Two platinum-based immunomodulators MUP and DMUP were synthesized to enhance the phagocytic activity of macrophages by blocking the CD47-SIRPα axis. These PtIV complexes not only showed high antiproliferative activity against a panel of human cancer cell lines, but also cooperated with human peripheral blood mononuclear cells (PBMCs) to suppress cancer cells. They acted as immune checkpoint inhibitors to modulate the immune responses of both cancer and immune cells. In particular, DMUP decreased the expression of CD47 in tumor tissues and promoted the polarization of macrophages from M2 to M1 phenotype in a mouse model of non-small cell lung cancer, thereby enhancing the anticancer effect. By interfering with DNA synthesis and stimulating immune system, DMUP takes the advantage of chemotherapy and immunotherapy to inhibit cancer cells. The dual efficacy of DMUP makes it a potential chemoimmunotherapeutic agent in cancer therapy.
Cancer cells are poorly immunogenic and have a wide range of mutations, which makes them unsuitable for use in vaccination treatment. Here, we show that elimination of CD47, a ligand for the myeloid cell inhibitory receptor SIRPα, from tumor cells by genetic deletion or antibody blocking, significantly improves the effectiveness of the immune response to tumour cells. In both solid and hematopoietic mouse tumor models, vaccination with tumor cells or tumor antigen-expressing cells, that lack CD47 or were pre-coated with anti-CD47 antibodies, achieved an antitumor immune response. The efficacy of this approach was synergistically enhanced when used in combination with anti-PD-1 antibodies. The induction of antitumor responses depends on SIRPα+CD11c+ DCs, which exhibit rapid expansion following introduction of CD47-deficient tumor cells. Our results indicate that CD47-deficient whole tumor cells can induce antitumor responses.
Cluster of differentiation 47 (CD47) is a widely expressed self-protection transmembrane protein that functions as a critical negative regulator to induce macrophage-mediated phagocytosis. Overexpression of CD47 enables cancer cells to escape immune surveillance and destruction by phagocytes both in solid tumours and leukaemia. The usefulness of anti-CD47 antibody has been demonstrated in multiple immunotherapies associated with macrophages. However, antigen sinks and toxicity induced by inadvertent binding to normal cells restrict its clinical applications. Here, a novel anti-human CD47 antibody, 4D10, was generated, and its variable regions were grafted onto a human IgG4 scaffold. Compared with the anti-CD47 antibody Hu5F9, the resulting chimeric antibody (c4D10) has consistently demonstrated good tolerance in in vitro and in vivo toxicity studies. Additionally, c4D10 showed effective therapeutic potential through inducing the eradication of human cancer cells. Thus, c4D10 is a promising candidate therapeutic antibody with higher efficacy and reduced side effects compared to earlier antibodies, and its use may reduce the dose-limiting toxicity of CD47 antagonists for immunotherapy.
CD47 has established roles in the immune system for regulating macrophage phagocytosis and lymphocyte activation, with growing evidence of its cell-intrinsic regulatory roles in natural killer and CD8+ T cells. CD47 limits antigen-dependent cytotoxic activities of human and murine CD8+ T cells, but its role in T cell activation kinetics remains unclear. Using in vitro and in vivo models, we show here that CD47 differentially regulates CD8+ T cell responses to short- versus long-term activation. Although CD47 was not required for T cell development in mice and early activation in vitro, short-term stimuli elevated pathogen-reactive gene expression and enhanced proliferation and the effector phenotypes of Cd47-deficient relative to Cd47-sufficient CD8+ T cells. In contrast, persistent TCR stimulation limited the effector phenotypes of Cd47 -/- CD8+ T cells and enhanced their apoptosis signature. CD8+ T cell expansion and activation in vivo induced by acute lymphocytic choriomeningitis virus (LCMV) infection did not differ in the absence of CD47. However, the frequency and effector phenotypes of Cd47-/- CD8+ T cells were constrained in chronic LCMV-infected as well as in mice bearing B16 melanoma tumors. Therefore, CD47 regulates CD8+ T cell activation, proliferation, and fitness in a context-dependent manner.
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