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Cancer Research Nov 2023The peritoneal cavity is a common site of gastric adenocarcinoma (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to current therapies and confers poor...
UNLABELLED
The peritoneal cavity is a common site of gastric adenocarcinoma (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to current therapies and confers poor prognosis, highlighting the need to identify new therapeutic targets. CD47 conveys a "don't eat me" signal to myeloid cells upon binding its receptor signal regulatory protein alpha (SIRPα), which helps tumor cells circumvent macrophage phagocytosis and evade innate immune responses. Previous studies demonstrated that the blockade of CD47 alone results in limited clinical benefits, suggesting that other target(s) might need to be inhibited simultaneously with CD47 to elicit a strong antitumor response. Here, we found that CD47 was highly expressed on malignant PC cells, and elevated CD47 was associated with poor prognosis. Galectin-3 (Gal3) expression correlated with CD47 expression, and coexpression of Gal3 and CD47 was significantly associated with diffuse type, poor differentiation, and tumor relapse. Depletion of Gal3 reduced expression of CD47 through inhibition of c-Myc binding to the CD47 promoter. Furthermore, injection of Gal3-deficient tumor cells into either wild-type and Lgals3-/- mice led to a reduction in M2 macrophages and increased T-cell responses compared with Gal3 wild-type tumor cells, indicating that tumor cell-derived Gal3 plays a more important role in GAC progression and phagocytosis than host-derived Gal3. Dual blockade of Gal3 and CD47 collaboratively suppressed tumor growth, increased phagocytosis, repolarized macrophages, and boosted T-cell immune responses. These data uncovered that Gal3 functions together with CD47 to suppress phagocytosis and orchestrate immunosuppression in GAC with PC, which supports exploring a novel combination therapy targeting Gal3 and CD47.
SIGNIFICANCE
Dual inhibition of CD47 and Gal3 enhances tumor cell phagocytosis and reprograms macrophages to overcome the immunosuppressive microenvironment and suppress tumor growth in peritoneal metastasis of gastric adenocarcinoma.
Topics: Animals; Mice; Adenocarcinoma; Antigens, Differentiation; CD47 Antigen; Galectin 3; Neoplasms; Peritoneal Neoplasms; Phagocytosis; Stomach Neoplasms; T-Lymphocytes; Tumor Microenvironment
PubMed: 37738407
DOI: 10.1158/0008-5472.CAN-23-0783 -
Nature Biomedical Engineering Sep 2023In solid tumours, the abundance of macrophages is typically associated with a poor prognosis. However, macrophage clusters in tumour-cell nests have been associated with...
In solid tumours, the abundance of macrophages is typically associated with a poor prognosis. However, macrophage clusters in tumour-cell nests have been associated with survival in some tumour types. Here, by using tumour organoids comprising macrophages and cancer cells opsonized via a monoclonal antibody, we show that highly ordered clusters of macrophages cooperatively phagocytose cancer cells to suppress tumour growth. In mice with poorly immunogenic tumours, the systemic delivery of macrophages with signal-regulatory protein alpha (SIRPα) genetically knocked out or else with blockade of the CD47-SIRPα macrophage checkpoint was combined with the monoclonal antibody and subsequently triggered the production of endogenous tumour-opsonizing immunoglobulin G, substantially increased the survival of the animals and helped confer durable protection from tumour re-challenge and metastasis. Maximizing phagocytic potency by increasing macrophage numbers, by tumour-cell opsonization and by disrupting the phagocytic checkpoint CD47-SIRPα may lead to durable anti-tumour responses in solid cancers.
Topics: Mice; Animals; CD47 Antigen; Receptors, Immunologic; Phagocytosis; Macrophages; Neoplasms; Antibodies, Monoclonal
PubMed: 37095318
DOI: 10.1038/s41551-023-01031-3 -
Cancer Cell Dec 2023While anti-CD47 antibodies hold promise for cancer immunotherapy, early-phase clinical trials have shown limited clinical benefit, suggesting that CD47 blockade alone...
While anti-CD47 antibodies hold promise for cancer immunotherapy, early-phase clinical trials have shown limited clinical benefit, suggesting that CD47 blockade alone might be insufficient for effective tumor control. Here, we investigate the contributions of the Fc domain of anti-CD47 antibodies required for optimal in vivo antitumor activity across multiple species-matched models, providing insights into the mechanisms behind the efficacy of this emerging class of therapeutic antibodies. Using a mouse model humanized for CD47, SIRPα, and FcγRs, we demonstrate that local administration of Fc-engineered anti-CD47 antibodies with enhanced binding to activating FcγRs promotes tumor infiltration of macrophages and antigen-specific T cells, while depleting regulatory T cells. These effects result in improved long-term systemic antitumor immunity and minimal on-target off-tumor toxicity. Our results highlight the importance of Fc optimization in the development of effective anti-CD47 therapies and provide an attractive strategy to enhance the activity of this promising immunotherapy.
Topics: Humans; CD47 Antigen; Immunotherapy; Macrophages; Neoplasms; Phagocytosis; Receptors, IgG; Antibodies; Animals; Mice
PubMed: 37977147
DOI: 10.1016/j.ccell.2023.10.007 -
Trends in Cancer Aug 2023Many patients with metastatic or treatment-resistant cancer have experienced improved outcomes after immunotherapy that targets adaptive immune checkpoints. However,... (Review)
Review
Many patients with metastatic or treatment-resistant cancer have experienced improved outcomes after immunotherapy that targets adaptive immune checkpoints. However, innate immune checkpoints, which can hinder the detection and clearance of malignant cells, are also crucial in tumor-mediated immune escape and may also serve as targets in cancer immunotherapy. In this review, we discuss the current understanding of immune evasion by cancer cells via disruption of phagocytic clearance, and the potential effects of blocking phagocytosis checkpoints on the activation of antitumor immune responses. We propose that a more effective combination immunotherapy strategy could be to exploit tumor-intrinsic processes that inhibit key innate immune surveillance processes, such as phagocytosis, and incorporate both innate and adaptive immune responses for treating patients with cancer.
Topics: Humans; Immunity, Innate; Phagocytosis; Neoplasms; Immunotherapy
PubMed: 37150626
DOI: 10.1016/j.trecan.2023.04.006 -
Developmental and Comparative Immunology Oct 2023Leukocyte immune-type receptors (LITRs) are a large family of teleost immunoregulatory receptor-types belonging to the immunoglobulin superfamily. These immune genes are... (Review)
Review
Leukocyte immune-type receptors (LITRs) are a large family of teleost immunoregulatory receptor-types belonging to the immunoglobulin superfamily. These immune genes are phylogenetically and syntenically related to Fc receptor-like protein genes (fcrls) present in other vertebrates, including amphibians, birds, mice, and man. In vitro-based functional analyses of LITRs, using transfection approaches, have shown that LITRs have diverse immunoregulatory potentials including the activation and inhibition of several innate immune effector responses such as cell-mediated killing responses, degranulation, cytokine secretion, and phagocytosis. The purpose of this mini review is to provide an overview of fish LITR-mediated immunoregulatory potentials obtained from various teleost model systems, including channel catfish, zebrafish, and goldfish. We will also describe preliminary characterization of a new goldish LITR-specific polyclonal antibody (pAb) and discuss the significance of this tool for further investigation of the functions of fish LITRs.
Topics: Mice; Animals; Zebrafish; Receptors, Immunologic; Phagocytosis; Immunity, Innate; Leukocytes
PubMed: 37414235
DOI: 10.1016/j.dci.2023.104768 -
Immunological Reviews Oct 2023Unconjugated monoclonal antibodies (mAb) have revolutionized the treatment of many types of cancer. Some of these mAbs promote the clearance of malignant cells via... (Review)
Review
Unconjugated monoclonal antibodies (mAb) have revolutionized the treatment of many types of cancer. Some of these mAbs promote the clearance of malignant cells via direct cytotoxic effects. More recently, antibody-dependent cellular phagocytosis (ADCP) has been appreciated as a major mechanism of action for a number of widely-used mAbs, including anti-CD20 (rituximab, obinutuzumab), anti-HER2 (trazituzumab), and anti-CD38 (daratumumab). However, as a monotherapy these ADCP-inducing mAbs produce insufficient levels of cytotoxicity in vivo and are not curative. As a result, these mAbs are most effectively used in combination therapies. The efficacy of these mAbs is further hampered by the apparent development of drug resistance by many patients. Here we will explore the role of ADCP in cancer immunotherapy and discuss the key factors that could limit the efficacy of ADCP-inducing mAbs in vivo. Finally, we will discuss current insights and approaches being applied to overcome these limitations.
Topics: Humans; Phagocytosis; Antibodies; Extracellular Space; Neoplasms; Immunotherapy
PubMed: 37602915
DOI: 10.1111/imr.13265 -
Immunological Reviews Oct 2023Phagocytosis is a fundamental immunobiological process responsible for the removal of harmful particulates. While the number of phagocytic events achieved by a single... (Review)
Review
Phagocytosis is a fundamental immunobiological process responsible for the removal of harmful particulates. While the number of phagocytic events achieved by a single phagocyte can be remarkable, exceeding hundreds per day, the same phagocytic cells are relatively long-lived. It should therefore be obvious that phagocytic meals must be resolved in order to maintain the responsiveness of the phagocyte and to avoid storage defects. In this article, we discuss the mechanisms involved in the resolution process, including solute transport pathways and membrane traffic. We describe how products liberated in phagolysosomes support phagocyte metabolism and the immune response. We also speculate on mechanisms involved in the redistribution of phagosomal metabolites back to circulation. Finally, we highlight the pathologies owed to impaired phagosome resolution, which range from storage disorders to neurodegenerative diseases.
Topics: Humans; Phagosomes; Phagocytosis; Phagocytes
PubMed: 37551912
DOI: 10.1111/imr.13260 -
Cell Host & Microbe Mar 2024Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence...
Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AMs). In SFB-negative mice, AMs were quickly depleted as RVI progressed. In contrast, AMs from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AMs from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AMs into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity.
Topics: Animals; Mice; Macrophages, Alveolar; Gastrointestinal Microbiome; Phagocytosis; Interferons; Bacteria; Virus Diseases
PubMed: 38295788
DOI: 10.1016/j.chom.2024.01.002 -
EMBO Molecular Medicine Dec 2023Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits...
Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage-mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3-associated phagocytosis (LAP), a non-canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G-protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL-induced efferocytosis, anti-colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3-associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease.
Topics: Mice; Animals; Phagocytosis; Signal Transduction; Inflammation; Macrophages; Colitis
PubMed: 37994307
DOI: 10.15252/emmm.202317815 -
International Journal of Molecular... Oct 2023Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells... (Review)
Review
Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells need to be removed in time to maintain the homeostasis of the organism and keep it healthy. This process is called efferocytosis. If the process fails, this may cause different types of diseases. More and more evidence suggests that a faulty efferocytosis process is closely related to the pathological processes of respiratory diseases. In this review, we will first introduce the process and the related mechanisms of efferocytosis of the macrophage. Secondly, we will propose some methods that can regulate the function of efferocytosis at different stages of the process. Next, we will discuss the role of efferocytosis in different lung diseases and the related treatment approaches. Finally, we will summarize the drugs that have been applied in clinical practice that can act upon efferocytosis, in order to provide new ideas for the treatment of lung diseases.
Topics: Humans; Apoptosis; Phagocytosis; Macrophages; Phagocytes; Lung Diseases; Respiration Disorders
PubMed: 37834319
DOI: 10.3390/ijms241914871