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Mowat C, Schiller D, Baker K. NLRP3 activation promotes cGAS/STING signaling and antitumor immunity by colorectal cancer cells. Cancer Immunol Immunother 2025; 74:238. [PMID: 40481953 PMCID: PMC12145389 DOI: 10.1007/s00262-025-04088-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Accepted: 05/12/2025] [Indexed: 06/11/2025]
Abstract
INTRODUCTION Colorectal cancer (CRC) is a highly prevalent and deadly disease that is largely refractory to immunotherapy. The only CRC subset that responds to these therapies is characterized by prevalent microsatellite instability (MSI), extensive CD8+ T cell infiltration and high expression of innate immune signaling pathways. Endogenous activation of the cGAS/STING pathway is essential for this CD8+ T cell antitumor response in MSI CRCs, suggesting that activating it in other CRCs could boost immunotherapy response rates. In contrast, activation of the NLRP3 inflammasome is typically associated with tumor-promoting inflammation although this has primarily been studied in immune cells. METHODS We used a mixture of flow cytometry, activation assays, in vivo orthotopic models and patient-derived organoids to investigate the effect of NLRP3 activation in CRC cells on cGAS/STING-mediated antitumor immunity. RESULTS Our results show that activation of the NLRP3 inflammasome specifically in CRC cells boosts cGAS/STING signaling in both MSI and non-MSI CRCs and that dual stimulation increases CD8+ T cell-mediated antitumor immunity. The ability of NLRP3 to enhance cGAS/STING signaling was specific and did not occur with activation of other innate immune pathways such as AIM2 or TLRs. Enhancement of cGAS/STING signaling by NLRP3 proceeded via a positive feedback loop that was inflammasome-independent and required early crosstalk between the signaling mediators and regulation of their gene expression. CONCLUSIONS Activation of NLRP3 specifically in CRC cells could be a promising strategy to boost antitumor immunity in otherwise immunotherapy resistant CRCs.
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Affiliation(s)
- Courtney Mowat
- Department of Oncology, University of Alberta, Edmonton, Canada
| | - Daniel Schiller
- Department of Surgery, Royal Alexandra Hospital, Edmonton, Canada
| | - Kristi Baker
- Department of Oncology, University of Alberta, Edmonton, Canada.
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.
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2
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Beffinger M, Schellhammer L, Taskoparan B, Deplazes S, Salazar U, Tatari N, Seehusen F, von Balthazar L, Zinner CP, Spath S, Shekarian T, Ritz MF, McDaid M, Egloff P, Zimmermann I, Okada H, Ward ES, Rohrer J, Seeger MA, Buch T, Hutter G, Vom Berg J. FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma. Nat Commun 2025; 16:4751. [PMID: 40404625 PMCID: PMC12098678 DOI: 10.1038/s41467-025-59971-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 05/09/2025] [Indexed: 05/24/2025] Open
Abstract
Glioblastoma remains a challenging indication for immunotherapy: the blood-brain barrier hampers accessibility for systemic treatments and the immunosuppressive microenvironment impedes immune attack. Intratumoral therapy with the proinflammatory cytokine interleukin-12 (IL-12) can revert immunosuppression but leakage into the circulation causes treatment-limiting toxicity. Here we engineer an IL-12Fc fusion cytokine with reduced binding to the neonatal Fc receptor FcRn. FcRn-silenced IL-12Fc avoids FcRn-mediated brain export, thus exhibits prolonged brain retention and reduced blood levels, which prevents toxicity. In murine glioblastoma, FcRn-silenced IL-12Fc induces more durable responses with negligible systemic cytokine exposure and boosts the efficacy of radio- and chemotherapy. It triggers anti-tumor responses independently of peripheral T cell influx or lymphopenia and leads to inflammatory polarization of the tumor microenvironment in patient-derived glioblastoma explants. FcRn-silencing of IL-12Fc may unlock the full potential of IL-12 for brain cancer therapy and could be further applied to containing the activity of other therapeutics targeting neurological diseases.
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Affiliation(s)
- Michal Beffinger
- Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland
- InCephalo AG, Allschwil, Switzerland
| | - Linda Schellhammer
- Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland
| | - Betül Taskoparan
- Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland
| | - Sereina Deplazes
- Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland
- InCephalo AG, Allschwil, Switzerland
| | - Ulisse Salazar
- Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland
| | - Nazanin Tatari
- Brain Tumor Immunotherapy and Biology Lab, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
| | - Frauke Seehusen
- Laboratory for Animal Model Pathology (LAMP), Institute of Veterinary Pathology, University of Zurich, Zurich, Switzerland
| | - Leopold von Balthazar
- Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Waedenswil, Switzerland
| | - Carl Philipp Zinner
- Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | | | - Tala Shekarian
- Brain Tumor Immunotherapy and Biology Lab, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
| | - Marie-Françoise Ritz
- Brain Tumor Immunotherapy and Biology Lab, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
| | - Marta McDaid
- Brain Tumor Immunotherapy and Biology Lab, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
| | - Pascal Egloff
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
| | - Iwan Zimmermann
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
- Linkster Therapeutics AG, Zurich, Switzerland
| | - Hideho Okada
- Department of Neurological Surgery, University of California, San Francisco, CA, USA
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
| | - E Sally Ward
- Cancer Sciences Unit, Centre for Cancer Immunology, University of Southampton, Southampton, UK
| | - Jack Rohrer
- Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Waedenswil, Switzerland
| | - Markus A Seeger
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
| | - Thorsten Buch
- Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland
| | - Gregor Hutter
- Brain Tumor Immunotherapy and Biology Lab, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
- Department of Neurosurgery, University Hospital of Basel, Basel, Switzerland
| | - Johannes Vom Berg
- Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland.
- InCephalo AG, Allschwil, Switzerland.
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3
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Gjølberg TT, Mester S, Calamera G, Telstad JS, Sandlie I, Andersen JT. Targeting the Neonatal Fc Receptor in Autoimmune Diseases: Pipeline and Progress. BioDrugs 2025; 39:373-409. [PMID: 40156757 PMCID: PMC12031853 DOI: 10.1007/s40259-025-00708-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2025] [Indexed: 04/01/2025]
Abstract
Autoimmune diseases are highly prevalent and affect people at all ages, women more often than men. The most prominent immunological manifestation is the production of antibodies directed against self-antigens. In many cases, these antibodies (Abs) drive the pathogenesis by attacking the body's own healthy cells, causing serious health problems that may be life threatening. Most autoantibodies are of the immunoglobulin G (IgG) isotype, which has a long plasma half-life and potent effector functions. Thus, there is a need for specific treatment options that rapidly eliminate these pathogenic IgG auto-Abs. In this review, we discuss how the neonatal Fc receptor (FcRn) acts as a regulator of the high levels of not only IgG Abs, but also albumin, by rescuing both these soluble proteins from cellular catabolism, and how a molecular and cellular understanding of this complex biology has spurred an intense interest in the development of FcRn-targeting strategies for the treatment of IgG-driven autoimmune diseases. We find that this emerging therapeutic class demonstrates efficacy within several autoimmune diseases with distinct pathophysiology. This offers hope for both new therapeutic avenues for highly prevalent diseases currently treated by other means, and rare diseases with no approved therapies to date. In addition, we elaborate on studies that have led to approval of the first FcRn antagonists, the clinical progress and structural design of molecules in the pipeline, their position in the overall therapeutic landscape of autoimmunity, the design of next-generation antagonists as well as the use of this receptor-targeting principle for other therapeutic applications.
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Affiliation(s)
- Torleif Tollefsrud Gjølberg
- Authera AS, 0349, Oslo, Norway.
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372, Oslo, Norway.
- Department of Immunology, Oslo University Hospital and University of Oslo, 0372, Oslo, Norway.
- Precision Immunotherapy Alliance (PRIMA), University of Oslo, Oslo, Norway.
| | - Simone Mester
- Authera AS, 0349, Oslo, Norway
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372, Oslo, Norway
- Department of Immunology, Oslo University Hospital and University of Oslo, 0372, Oslo, Norway
- Precision Immunotherapy Alliance (PRIMA), University of Oslo, Oslo, Norway
| | | | | | - Inger Sandlie
- Department of Biosciences, University of Oslo, 0316, Oslo, Norway
| | - Jan Terje Andersen
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0372, Oslo, Norway.
- Department of Immunology, Oslo University Hospital and University of Oslo, 0372, Oslo, Norway.
- Precision Immunotherapy Alliance (PRIMA), University of Oslo, Oslo, Norway.
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Bussel JB, Cines DB, Blumberg RS. Neonatal Fc Receptor - Biology and Therapeutics. N Engl J Med 2025; 392:1621-1635. [PMID: 40267427 DOI: 10.1056/nejmra2312718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/25/2025]
Affiliation(s)
| | - Douglas B Cines
- Departments of Pathology and Laboratory Medicine and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Richard S Blumberg
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston
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Fiore NT, Willcox KF, Dayani D, Zuberi YA, Heijnen CJ, Grace PM. Reducing IgG accumulation via neonatal Fc receptor (FcRn) blockade relieves neuropathic pain. Brain Behav Immun 2025; 125:371-387. [PMID: 39870199 PMCID: PMC11903150 DOI: 10.1016/j.bbi.2025.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 01/16/2025] [Accepted: 01/21/2025] [Indexed: 01/29/2025] Open
Abstract
Preclinical and clinical studies have established that autoreactive immunoglobulin G (IgG) can drive neuropathic pain. We recently demonstrated that sciatic nerve chronic constriction injury (CCI) in male and female mice results in the production of pronociceptive IgG, which accumulates around the lumbar region, including within the dorsal root ganglia (DRG) and spinal cord, facilitating the development of neuropathic pain. These data raise the intriguing possibility that neuropathic pain may be alleviated by reducing the accumulation of IgG. To this end, we tested whether biologic inhibition or genetic deletion of the neonatal Fc receptor (FcRn) would attenuate mechanical hypersensitivity (allodynia) and IgG deposition induced by CCI. FcRn are prominently expressed on myeloid and endothelial cells and extend the half-life of IgG via pinocytosis and recycling into the extracellular milieu. We show here that administration of the FcRn blocker efgartigimod either 7- or 28-days post-CCI relieved allodynia among both male and female mice, compared to the Fc fragment control. Efgartigimod, administered systemically (intraperitoneal) or to the lumbar region (intrathecal), attenuated mechanical allodynia for at least one month. CCI-induced allodynia was similarly reduced in FcRn-deficient (FcRn-) mice compared to wild-type mice. Biologic inhibition or genetic deletion of FcRn also reduced CCI-induced accumulation of IgG on macrophages and neurons in lumbar DRG, as well as microglia in the lumbar dorsal spinal cord. Expression of the Fc receptor γ subunit (FcRγ) was reduced in efgartigimod-treated or FcRn- mice post-CCI compared to controls. The FcRγ subunit is a key component of Fc gamma receptors (FcγRs), which are activated by IgG immune complexes. In macrophage cultures stimulated by IgG immune complexes, FcRn blockade also dampened FcγR-dependent production of proinflammatory cytokines. Collectively, our study demonstrates that FcRn blockade or deletion alleviates mechanical allodynia and reduces IgG accumulation after CCI, attenuating pronociceptive IgG-FcγR signaling around the lumbar region. Strategies to block FcRn and reduce IgG recycling warrant further investigation as potential treatments for IgG-mediated neuropathic pain.
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Affiliation(s)
- Nathan T Fiore
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Kendal F Willcox
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Dorsa Dayani
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Younus A Zuberi
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, USA
| | - Cobi J Heijnen
- Department of Psychological Sciences, Rice University, Houston, USA
| | - Peter M Grace
- Laboratories of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, USA.
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Martin J, Rittersberger R, Treitler S, Kopp P, Ibraimi A, Koslowski G, Sickinger M, Dabbars A, Schindowski K. Characterization of a primary cellular airway model for inhalative drug delivery in comparison with the established permanent cell lines CaLu3 and RPMI 2650. IN VITRO MODELS 2024; 3:183-203. [PMID: 39872698 PMCID: PMC11756470 DOI: 10.1007/s44164-024-00079-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 11/03/2024] [Accepted: 11/04/2024] [Indexed: 01/30/2025]
Abstract
Purpose For optimization of respiratory drug delivery, the selection of suitable in vitro cell models plays an important role in predicting the efficacy and safety of (bio)pharmaceutics and pharmaceutical formulations. Therefore, an in-depth comparison of different primary and permanent in vitro cellular airway models was performed with a focus on selecting a suitable model for inhalative antibodies. Methods Primary cells isolated from the porcine trachea were compared with the established human cell lines CaLu3 and RPMI 2650. The in vitro models were characterized for different epithelial markers by real-time quantitative polymerase chain reaction, which provides insight into the cellular composition of each model. For a few selected markers, the results from RT-qPCR were confirmed via immunofluorescence. Barrier integrity was assessed by transepithelial electrical resistance measurements and FITC-dextran permeability. Results Primary cell models retain key features of the respiratory epithelium, e.g., the formation of a tight epithelial barrier, mucin production, and the presence of club/basal cells. Furthermore, the expression of Fc receptors in the primary cell models closely resembles that in respiratory mucosal tissue, an essential parameter to consider when developing therapeutic antibodies for inhalation. Conclusion The study underlines the importance of selecting wisely appropriate in vitro models. Despite the greater effort and variability in cultivating primary airway cells, they are far superior to permanent cells and a suitable model for drug development. Supplementary Information The online version contains supplementary material available at 10.1007/s44164-024-00079-y.
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Affiliation(s)
- Janik Martin
- Institute of Applied Biotechnology, University of Applied Science Biberach, Hubertus-Liebrecht Strasse 35, 88400 Biberach, Germany
- Faculty of Natural Science, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany
| | - Rebecca Rittersberger
- Institute of Applied Biotechnology, University of Applied Science Biberach, Hubertus-Liebrecht Strasse 35, 88400 Biberach, Germany
- Faculty of Natural Science, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany
| | - Simon Treitler
- Institute of Applied Biotechnology, University of Applied Science Biberach, Hubertus-Liebrecht Strasse 35, 88400 Biberach, Germany
| | - Patrick Kopp
- Institute of Applied Biotechnology, University of Applied Science Biberach, Hubertus-Liebrecht Strasse 35, 88400 Biberach, Germany
| | - Anit Ibraimi
- Institute of Applied Biotechnology, University of Applied Science Biberach, Hubertus-Liebrecht Strasse 35, 88400 Biberach, Germany
- Justus-Von-Liebig-Schule, Von-Kilian-Straße 5, 79762 Waldshut-Tiengen, Germany
| | - Gabriel Koslowski
- Institute of Applied Biotechnology, University of Applied Science Biberach, Hubertus-Liebrecht Strasse 35, 88400 Biberach, Germany
| | - Max Sickinger
- Institute of Applied Biotechnology, University of Applied Science Biberach, Hubertus-Liebrecht Strasse 35, 88400 Biberach, Germany
| | - Annabelle Dabbars
- Institute of Applied Biotechnology, University of Applied Science Biberach, Hubertus-Liebrecht Strasse 35, 88400 Biberach, Germany
| | - Katharina Schindowski
- Institute of Applied Biotechnology, University of Applied Science Biberach, Hubertus-Liebrecht Strasse 35, 88400 Biberach, Germany
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7
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Hematianlarki M, Nimmerjahn F. Immunomodulatory and anti-inflammatory properties of immunoglobulin G antibodies. Immunol Rev 2024; 328:372-386. [PMID: 39340138 PMCID: PMC11659946 DOI: 10.1111/imr.13404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2024]
Abstract
Antibodies provide an essential layer of protection from infection and reinfection with microbial pathogens. An impaired ability to produce antibodies results in immunodeficiency and necessitates the constant substitution with pooled serum antibodies from healthy donors. Among the five antibody isotypes in humans and mice, immunoglobulin G (IgG) antibodies are the most potent anti-microbial antibody isotype due to their long half-life, their ability to penetrate almost all tissues and due to their ability to trigger a wide variety of effector functions. Of note, individuals suffering from IgG deficiency frequently produce self-reactive antibodies, suggesting that a normal serum IgG level also may contribute to maintaining self-tolerance. Indeed, the substitution of immunodeficient patients with pooled serum IgG fractions from healthy donors, also referred to as intravenous immunoglobulin G (IVIg) therapy, not only protects the patient from infection but also diminishes autoantibody induced pathology, providing more direct evidence that IgG antibodies play an active role in maintaining tolerance during the steady state and during resolution of inflammation. The aim of this review is to discuss different conceptual models that may explain how serum IgG or IVIg can contribute to maintaining a balanced immune response. We will focus on pathways depending on the IgG fragment crystallizable (Fc) as pre-clinical data in various mouse model systems as well as human clinical data have demonstrated that the IgG Fc-domain recapitulates the ability of intact IVIg with respect to its ability to trigger resolution of inflammation. We will further discuss how the findings already have or are in the process of being translated to novel therapeutic approaches to substitute IVIg in treating autoimmune inflammation.
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Affiliation(s)
- Marjan Hematianlarki
- Division of Genetics, Department of BiologyFriedrich Alexander University Erlangen‐NürnbergErlangenGermany
| | - Falk Nimmerjahn
- Division of Genetics, Department of BiologyFriedrich Alexander University Erlangen‐NürnbergErlangenGermany
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8
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Alekseeva ON, Hoa LT, Vorobyev PO, Kochetkov DV, Gumennaya YD, Naberezhnaya ER, Chuvashov DO, Ivanov AV, Chumakov PM, Lipatova AV. Receptors and Host Factors for Enterovirus Infection: Implications for Cancer Therapy. Cancers (Basel) 2024; 16:3139. [PMID: 39335111 PMCID: PMC11430599 DOI: 10.3390/cancers16183139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/29/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
Enteroviruses, with their diverse clinical manifestations ranging from mild or asymptomatic infections to severe diseases such as poliomyelitis and viral myocarditis, present a public health threat. However, they can also be used as oncolytic agents. This review shows the intricate relationship between enteroviruses and host cell factors. Enteroviruses utilize specific receptors and coreceptors for cell entry that are critical for infection and subsequent viral replication. These receptors, many of which are glycoproteins, facilitate virus binding, capsid destabilization, and internalization into cells, and their expression defines virus tropism towards various types of cells. Since enteroviruses can exploit different receptors, they have high oncolytic potential for personalized cancer therapy, as exemplified by the antitumor activity of certain enterovirus strains including the bioselected non-pathogenic Echovirus type 7/Rigvir, approved for melanoma treatment. Dissecting the roles of individual receptors in the entry of enteroviruses can provide valuable insights into their potential in cancer therapy. This review discusses the application of gene-targeting techniques such as CRISPR/Cas9 technology to investigate the impact of the loss of a particular receptor on the attachment of the virus and its subsequent internalization. It also summarizes the data on their expression in various types of cancer. By understanding how enteroviruses interact with specific cellular receptors, researchers can develop more effective regimens of treatment, offering hope for more targeted and efficient therapeutic strategies.
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Affiliation(s)
- Olga N. Alekseeva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.N.A.); (P.O.V.); (D.V.K.); (Y.D.G.); (E.R.N.); (D.O.C.); (P.M.C.)
| | - Le T. Hoa
- Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Pavel O. Vorobyev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.N.A.); (P.O.V.); (D.V.K.); (Y.D.G.); (E.R.N.); (D.O.C.); (P.M.C.)
| | - Dmitriy V. Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.N.A.); (P.O.V.); (D.V.K.); (Y.D.G.); (E.R.N.); (D.O.C.); (P.M.C.)
| | - Yana D. Gumennaya
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.N.A.); (P.O.V.); (D.V.K.); (Y.D.G.); (E.R.N.); (D.O.C.); (P.M.C.)
| | - Elizaveta R. Naberezhnaya
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.N.A.); (P.O.V.); (D.V.K.); (Y.D.G.); (E.R.N.); (D.O.C.); (P.M.C.)
| | - Denis O. Chuvashov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.N.A.); (P.O.V.); (D.V.K.); (Y.D.G.); (E.R.N.); (D.O.C.); (P.M.C.)
| | - Alexander V. Ivanov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.N.A.); (P.O.V.); (D.V.K.); (Y.D.G.); (E.R.N.); (D.O.C.); (P.M.C.)
| | - Peter M. Chumakov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.N.A.); (P.O.V.); (D.V.K.); (Y.D.G.); (E.R.N.); (D.O.C.); (P.M.C.)
| | - Anastasia V. Lipatova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.N.A.); (P.O.V.); (D.V.K.); (Y.D.G.); (E.R.N.); (D.O.C.); (P.M.C.)
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Qian S, Zhang D, Yang Z, Li R, Zhang X, Gao F, Yu L. The role of immunoglobulin transport receptor, neonatal Fc receptor in mucosal infection and immunity and therapeutic intervention. Int Immunopharmacol 2024; 138:112583. [PMID: 38971109 DOI: 10.1016/j.intimp.2024.112583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 06/15/2024] [Accepted: 06/25/2024] [Indexed: 07/08/2024]
Abstract
The neonatal Fc receptor (FcRn) can transport IgG and antigen-antibody complexes participating in mucosal immune responses that protect the host from most pathogens' invasion via the respiratory, digestive, and urogenital tracts. FcRn expression can be triggered upon stimulation with pathogenic invasion on mucosal surfaces, which may significantly modulate the innate immune response of the host. As an immunoglobulin transport receptor, FcRn is implicated in the pathophysiology of immune-related diseases such as infection and autoimmune disorders. In this review, we thoroughly summarize the recent advancement of FcRn in mucosal immunity and its therapeutic strategy. This includes insights into its regulation mechanisms of FcRn expression influenced by pathogens, its emerging role in mucosal immunity and its potential probability as a therapeutic target in infection and autoimmune diseases.
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Affiliation(s)
- Shaoju Qian
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan 453003, China
| | - Danqiong Zhang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan 453003, China
| | - Zishan Yang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan 453003, China
| | - Ruixue Li
- Department of Otolaryngology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China
| | - Xuehan Zhang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan 453003, China
| | - Feifei Gao
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan 453003, China
| | - Lili Yu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan 453003, China.
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10
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Gleeson PJ, Monteiro RC. The Role of Mucosal Immunity: What Can We Learn From Animal and Human Studies? Semin Nephrol 2024; 44:151566. [PMID: 40082160 DOI: 10.1016/j.semnephrol.2025.151566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Immunoglobulin A (IgA) is a key actor in the mucosal immune system, which moderates interactions between the host and environmental factors such as food antigens and commensal microorganisms. The pathogenesis of IgA nephropathy (IgAN) involves a multistep process starting with deglycosylation of mucosally derived, polymeric IgA1 (dg-IgA1) that reaches the circulation. Modified O-glycans on dg-IgA1 are targeted by IgG-autoantibodies, leading to the formation of circulating immune complexes that deposit in the glomerular mesangium. Infections of mucosal surfaces trigger flares of primary IgAN, while inflammatory bowel disease and liver cirrhosis are important causes of secondary IgAN, supporting a mucosal source of nephritogenic IgA1. In the presence of microbial pathogens or food antigens, activated dendritic cells in the gut mucosa induce T-cell-dependent or T-cell-independent B-cell differentiation into IgA-secreting plasma cells. Herein we review the literature concerning mucosal immune function and how it is altered in this disease. We discuss recent evidence supporting a causal role of gut microbiota dysbiosis in IgAN pathogenesis.
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Affiliation(s)
- Patrick J Gleeson
- Paris Cité University, Center for Research on Inflammation, Paris, France; Inserm, UMR1149; CNRS EMR8252; Inflamex Laboratory of Excellence; Nephrology Department.
| | - Renato C Monteiro
- Paris Cité University, Center for Research on Inflammation, Paris, France; Inserm, UMR1149; CNRS EMR8252; Inflamex Laboratory of Excellence; Immunology laboratory of Bichat hospital, Paris, France
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11
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Boulard P, Azzopardi N, Levard R, Cornec JM, Lamamy J, Prieur B, Demattei MV, Watier H, Gatault P, Gouilleux-Gruart V. Albumin influences leucocyte FcRn expression in the early days of kidney transplantation. Clin Exp Immunol 2024; 216:307-317. [PMID: 38353127 PMCID: PMC11097912 DOI: 10.1093/cei/uxae011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 12/28/2023] [Accepted: 02/08/2024] [Indexed: 05/18/2024] Open
Abstract
FcRn, a receptor originally known for its involvement in IgG and albumin transcytosis and recycling, is also important in the establishment of the innate and adaptive immune response. Dysregulation of the immune response has been associated with variations in FcRn expression, as observed in cancer. Recently, a link between autophagy and FcRn expression has been demonstrated. Knowing that autophagy is strongly involved in the development of reperfusion injury in kidney transplantation and that albuminemia is transiently decreased in the first 2 weeks after transplantation, we investigated variations in FcRn expression after kidney transplantation. We monitored FcRn levels by flow cytometry in leukocytes from 25 renal transplant patients and considered parameters such as albumin concentrations, estimated glomerular filtration rate, serum creatinine, serum IgG levels, and ischaemia/reperfusion time. Two groups of patients could be distinguished according to their increased or non-increased FcRn expression levels between days 2 and 6 (d2-d6) post-transplantation. Leukocyte FcRn expression at d2-d6 was correlated with albumin concentrations at d0-d2. These results suggest that albumin concentrations at d0-d2 influence FcRn expression at d2-d6, raising new questions about the mechanisms underlying these original observations.
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Affiliation(s)
- Pierre Boulard
- Centre d’Étude des Pathologies Respiratoires (CEPR) U1100 INSERM, Tours, France
- Laboratoire d’immunologie, CHU de Tours, Tours,France
| | | | - Romain Levard
- Laboratoire d’immunologie, CHU de Tours, Tours,France
| | | | - Juliette Lamamy
- EA7501 GICC, Faculté de Médecine, Université de Tours, Tours,France
| | | | | | - Hervé Watier
- Laboratoire d’immunologie, CHU de Tours, Tours,France
- EA7501 GICC, Faculté de Médecine, Université de Tours, Tours,France
| | - Philippe Gatault
- EA4245 T2I, Faculté de Médecine, Université de Tours, Tours,France
- Service de Néphrologie, CHU de Tours, Tours,France
| | - Valérie Gouilleux-Gruart
- Laboratoire d’immunologie, CHU de Tours, Tours,France
- EA7501 GICC, Faculté de Médecine, Université de Tours, Tours,France
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12
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Macri C, Paxman M, Jenika D, Lin XP, Elahi Z, Gleeson PA, Caminschi I, Lahoud MH, Villadangos JA, Mintern JD. FcRn regulates antigen presentation in dendritic cells downstream of DEC205-targeted vaccines. NPJ Vaccines 2024; 9:76. [PMID: 38594284 PMCID: PMC11003989 DOI: 10.1038/s41541-024-00854-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 02/29/2024] [Indexed: 04/11/2024] Open
Abstract
Dendritic cell (DC)-targeted vaccination is a new mode of antigen delivery that relies on the use of monoclonal antibodies (mAb) to target antigen to specific DC subsets. The neonatal Fc receptor (FcRn) is a non-classical Fc receptor that binds to immunoglobulin G (IgG) in acidified endosomes and controls its intracellular transport and recycling. FcRn is known to participate in the antigen presentation of immune complexes, however its contribution to DC-targeted vaccination has not previously been examined. Here we have investigated the role of FcRn in antigen presentation using antigen conjugated to IgG mAb which target specific DC receptors, including DEC205 and Clec9A expressed by the conventional DC 1 (cDC1) subset. We show that FcRn is expressed at high levels by cDC1, both at steady-state and following activation and plays a significant role in MHC I cross-presentation and MHC II presentation of antigens that are targeted to cDC1 via mAb specific for DEC205. This effect of FcRn is intrinsic to cDC1 and FcRn impacts the efficacy of anti-DEC205-mediated vaccination against B cell lymphoma. In contrast, FcRn does not impact presentation of antigens targeted to Clec9A and does not regulate presentation of cell-associated antigen. These data highlight a new and unique role of FcRn in controlling the immunogenicity of anti-DEC205-based vaccination, with consequences for exploiting this pathway to improve DC-targeted vaccine outcomes.
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Affiliation(s)
- Christophe Macri
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne, Victoria, 3010, Australia
| | - Matthew Paxman
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne, Victoria, 3010, Australia
| | - Devi Jenika
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne, Victoria, 3010, Australia
| | - Xiao Peng Lin
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne, Victoria, 3010, Australia
| | - Zahra Elahi
- Department of Anatomy and Physiology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Paul A Gleeson
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne, Victoria, 3010, Australia
| | - Irina Caminschi
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, 3010, Australia
- Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia
| | - Mireille H Lahoud
- Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia
| | - Jose A Villadangos
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne, Victoria, 3010, Australia
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Justine D Mintern
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, The University of Melbourne, Victoria, 3010, Australia.
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13
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Guo Y, Remaily BC, Thomas J, Kim K, Kulp SK, Mace TA, Ganesan LP, Owen DH, Coss CC, Phelps MA. Antibody Drug Clearance: An Underexplored Marker of Outcomes with Checkpoint Inhibitors. Clin Cancer Res 2024; 30:942-958. [PMID: 37921739 PMCID: PMC10922515 DOI: 10.1158/1078-0432.ccr-23-1683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/23/2023] [Accepted: 10/13/2023] [Indexed: 11/04/2023]
Abstract
Immune-checkpoint inhibitor (ICI) therapy has dramatically changed the clinical landscape for several cancers, and ICI use continues to expand across many cancer types. Low baseline clearance (CL) and/or a large reduction of CL during treatment correlates with better clinical response and longer survival. Similar phenomena have also been reported with other monoclonal antibodies (mAb) in cancer and other diseases, highlighting a characteristic of mAb clinical pharmacology that is potentially shared among various mAbs and diseases. Though tempting to attribute poor outcomes to low drug exposure and arguably low target engagement due to high CL, such speculation is not supported by the relatively flat exposure-response relationship of most ICIs, where a higher dose or exposure is not likely to provide additional benefit. Instead, an elevated and/or increasing CL could be a surrogate marker of the inherent resistant phenotype that cannot be reversed by maximizing drug exposure. The mechanisms connecting ICI clearance, therapeutic efficacy, and resistance are unclear and likely to be multifactorial. Therefore, to explore the potential of ICI CL as an early marker for efficacy, this review highlights the similarities and differences of CL characteristics and CL-response relationships for all FDA-approved ICIs, and we compare and contrast these to selected non-ICI mAbs. We also discuss underlying mechanisms that potentially link mAb CL with efficacy and highlight existing knowledge gaps and future directions where more clinical and preclinical investigations are warranted to clearly understand the value of baseline and/or time-varying CL in predicting response to ICI-based therapeutics.
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Affiliation(s)
- Yizhen Guo
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH
| | - Bryan C. Remaily
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH
| | - Justin Thomas
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH
| | - Kyeongmin Kim
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH
| | - Samuel K. Kulp
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH
| | - Thomas A. Mace
- Department of Internal Medicine, Division of Rheumatology and Immunology, Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Latha P. Ganesan
- Department of Internal Medicine, Division of Rheumatology and Immunology, Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Dwight H. Owen
- Division of Medical Oncology, Ohio State University Wexner Medical Center, James Cancer Hospital and Solove Research Institute, Columbus, OH
| | - Christopher C. Coss
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH
| | - Mitch A. Phelps
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH
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14
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Armitage CW, O'Meara CP, Bryan ER, Kollipara A, Trim LK, Hickey D, Carey AJ, Huston WM, Donnelly G, Yazdani A, Blumberg RS, Beagley KW. IgG exacerbates genital chlamydial pathology in females by enhancing pathogenic CD8 + T cell responses. Scand J Immunol 2024; 99:e13331. [PMID: 38441219 PMCID: PMC10909563 DOI: 10.1111/sji.13331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/25/2023] [Accepted: 09/11/2023] [Indexed: 03/07/2024]
Abstract
Chlamydia trachomatis infections are an important sexually transmitted infection that can lead to inflammation, scarring and hydrosalpinx/infertility. However, infections are commonly clinically asymptomatic and do not receive treatment. The underlying cause of asymptomatic immunopathology remains unknown. Here, we demonstrate that IgG produced during male infection enhanced the incidence of immunopathology and infertility in females. Human endocervical cells expressing the neonatal Fc Receptor (FcRn) increased translocation of human IgG-opsonized C. trachomatis. Using total IgG purified from infected male mice, we opsonized C. muridarum and then infected female mice, mimicking sexual transmission. Following infection, IgG-opsonized Chlamydia was found to transcytose the epithelial barrier in the uterus, where it was phagocytosed by antigen-presenting cells (APCs) and trafficked to the draining lymph nodes. APCs then expanded both CD4+ and CD8+ T cell populations and caused significantly more infertility in female mice infected with non-opsonized Chlamydia. Enhanced phagocytosis of IgG-opsonized Chlamydia significantly increased pro-inflammatory signalling and T cell proliferation. As IgG is transcytosed by FcRn, we utilized FcRn-/- mice and observed that shedding kinetics of Chlamydia were only affected in FcRn-/- mice infected with IgG-opsonized Chlamydia. Depletion of CD8+ T cells in FcRn-/- mice lead to a significant reduction in the incidence of infertility. Taken together, these data demonstrate that IgG seroconversion during male infection can amplify female immunopathology, dependent on FcRn transcytosis, APC differentiation and enhanced CD8 T cell responses.
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Affiliation(s)
- Charles W. Armitage
- Centre for Immunology and Infection Control and School of Biomedical SciencesQueensland University of Technology (QUT)BrisbaneQueenslandAustralia
| | - Connor P. O'Meara
- Centre for Immunology and Infection Control and School of Biomedical SciencesQueensland University of Technology (QUT)BrisbaneQueenslandAustralia
- Drop Bio Ltd, School of Biotechnology and Biomolecular Sciences (BABS)University of New South WalesSydneyNew South WalesAustralia
| | - Emily R. Bryan
- Centre for Immunology and Infection Control and School of Biomedical SciencesQueensland University of Technology (QUT)BrisbaneQueenslandAustralia
| | - Avinash Kollipara
- Centre for Immunology and Infection Control and School of Biomedical SciencesQueensland University of Technology (QUT)BrisbaneQueenslandAustralia
| | - Logan K. Trim
- Centre for Immunology and Infection Control and School of Biomedical SciencesQueensland University of Technology (QUT)BrisbaneQueenslandAustralia
| | - Danica Hickey
- Centre for Immunology and Infection Control and School of Biomedical SciencesQueensland University of Technology (QUT)BrisbaneQueenslandAustralia
| | - Alison J. Carey
- Centre for Immunology and Infection Control and School of Biomedical SciencesQueensland University of Technology (QUT)BrisbaneQueenslandAustralia
| | - Wilhelmina M. Huston
- School of Life SciencesUniversity of Technology (UTS) SydneyUltimoNew South WalesAustralia
| | - Gavin Donnelly
- Queensland Fertility Group (QFG)BrisbaneQueenslandAustralia
| | - Anusch Yazdani
- Queensland Fertility Group (QFG)BrisbaneQueenslandAustralia
| | - Richard S. Blumberg
- Division of Gastroenterology, Department of MedicineBrigham & Women's Hospital, Harvard Medical SchoolBostonMassachusettsUSA
| | - Kenneth W. Beagley
- Centre for Immunology and Infection Control and School of Biomedical SciencesQueensland University of Technology (QUT)BrisbaneQueenslandAustralia
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15
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Dylewski JF, Haddad G, Blaine J. Exploiting the neonatal crystallizable fragment receptor to treat kidney disease. Kidney Int 2024; 105:54-64. [PMID: 38707675 PMCID: PMC11068363 DOI: 10.1016/j.kint.2023.09.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 09/11/2023] [Accepted: 09/25/2023] [Indexed: 05/07/2024]
Abstract
The neonatal Fc receptor (FcRn) was initially discovered as the receptor that allowed passive immunity in newborns by transporting maternal IgG through the placenta and enterocytes. Since its initial discovery, FcRn has been found to exist throughout all stages of life and in many different cell types. Beyond passive immunity, FcRn is necessary for intrinsic albumin and IgG recycling and is important for antigen processing and presentation. Given its multiple important roles, FcRn has been utilized in many disease treatments including a new class of agents that were developed to inhibit FcRn for treatment of a variety of autoimmune diseases. Certain cell populations within the kidney also express high levels of this receptor. Specifically, podocytes, proximal tubule epithelial cells, and vascular endothelial cells have been found to utilize FcRn. In this review, we summarize what is known about FcRn and its function within the kidney. We also discuss how FcRn has been used for therapeutic benefit, including how newer FcRn inhibiting agents are being used to treat autoimmune diseases. Lastly, we will discuss what renal diseases may respond to FcRn inhibitors and how further work studying FcRn within the kidney may lead to therapies for kidney diseases.
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Affiliation(s)
- James F. Dylewski
- Division of Renal Disease and Hypertension, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
- Division of Nephrology, Denver Health Medical Center, Denver, CO, USA
| | - George Haddad
- Division of Renal Disease and Hypertension, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Judith Blaine
- Division of Renal Disease and Hypertension, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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16
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Vu TT, Kim K, Manna M, Thomas J, Remaily BC, Montgomery EJ, Costa T, Granchie L, Xie Z, Guo Y, Chen M, Castillo AMM, Kulp SK, Mo X, Nimmagadda S, Gregorevic P, Owen DH, Ganesan LP, Mace TA, Coss CC, Phelps MA. Decoupling FcRn and tumor contributions to elevated immune checkpoint inhibitor clearance in cancer cachexia. Pharmacol Res 2024; 199:107048. [PMID: 38145833 PMCID: PMC10798214 DOI: 10.1016/j.phrs.2023.107048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 12/27/2023]
Abstract
High baseline clearance of immune checkpoint inhibitors (ICIs), independent of dose or systemic exposure, is associated with cachexia and poor outcomes in cancer patients. Mechanisms linking ICI clearance, cachexia and ICI therapy failure are unknown. Here, we evaluate in four murine models and across multiple antibodies whether altered baseline catabolic clearance of administered antibody requires a tumor and/or cachexia and whether medical reversal of cachexia phenotype can alleviate altered clearance. Key findings include mild cachexia phenotype and lack of elevated pembrolizumab clearance in the MC38 tumor-bearing model. We also observed severe cachexia and decreased, instead of increased, baseline pembrolizumab clearance in the tumor-free cisplatin-induced cachexia model. Liver Fcgrt expression correlated with altered baseline catabolic clearance, though elevated clearance was still observed with antibodies having no (human IgA) or reduced (human H310Q IgG1) FcRn binding. We conclude cachexia phenotype coincides with altered antibody clearance, though tumor presence is neither sufficient nor necessary for altered clearance in immunocompetent mice. Magnitude and direction of clearance alteration correlated with hepatic Fcgrt, suggesting changes in FcRn expression and/or recycling function may be partially responsible, though factors beyond FcRn also contribute to altered clearance in cachexia.
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Affiliation(s)
- Trang T Vu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Kyeongmin Kim
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Millennium Manna
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Justin Thomas
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Bryan C Remaily
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Emma J Montgomery
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Travis Costa
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA
| | - Lauren Granchie
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Zhiliang Xie
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Yizhen Guo
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Min Chen
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Alyssa Marie M Castillo
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Samuel K Kulp
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Xiaokui Mo
- Center for Biostatistics, Ohio State University, Columbus, OH, USA; Pelotonia Institute for Immuno-Oncology, OSUCCC - James, The Ohio State University, Columbus, OH , USA
| | - Sridhar Nimmagadda
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Paul Gregorevic
- Department of Anatomy & Physiology and Centre for Muscle Research, The University of Melbourne, Parkville, VIC, Australia
| | - Dwight H Owen
- Pelotonia Institute for Immuno-Oncology, OSUCCC - James, The Ohio State University, Columbus, OH , USA; The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Latha P Ganesan
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Thomas A Mace
- Pelotonia Institute for Immuno-Oncology, OSUCCC - James, The Ohio State University, Columbus, OH , USA; The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - Christopher C Coss
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA; The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
| | - Mitch A Phelps
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA; Pelotonia Institute for Immuno-Oncology, OSUCCC - James, The Ohio State University, Columbus, OH , USA; The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
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17
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Song DH, Yang J, Kim CH, Kim MH, Jo JY, Baek JC. FcRn Expression in Endometrial Cancer and Its Association with Clinicopathologic Features. Diagnostics (Basel) 2023; 13:3660. [PMID: 38132243 PMCID: PMC10742809 DOI: 10.3390/diagnostics13243660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Endometrial cancer (EC) has robust molecular diagnostic evidence that correlates well with prognosis. In various types of cancers, FcRn has been identified as an early marker for prognosis. This study aims to assess FcRn expression and its association with clinicopathological features in endometrial cancer. MATERIALS AND METHODS We employed a tissue microarray (TMA) from a retrospective cohort of 41 patients diagnosed with endometrioid endometrial cancer post hysterectomy between January 2002 and December 2009 at Gyeongsang National University Hospital. Relevant clinical data collection for the cohort involved reviewing patients' electronic medical charts. FcRn expression in microarrays of patient EC tissue was examined in conjunction with clinicopathologic data. Experiments, including siRNA knock-down, PCR mRNA semiquantification, Western blot, and confluence change tests, were conducted on the Ishikawa cell line. RESULTS The overall FcRn expression rate in EC patients was 41.8%. FIGO stage showed a statistically significant relationship with FcRn expression, while age, lymphovascular invasion, myometrial invasion, and tumor size had no effect. In endometrioid cancer cells of FIGO stage IA, FcRn was less frequently expressed than in other high-staged EC patients (p = 0.021). In experiments on the Ishikawa cell line, the siRNA knock-down group exhibited quantitatively lower FCGRT mRNA expression and lower FcRn protein signal compared to the scrambled RNA control group. The change in confluence over time measured at three hotspots did not show a significant difference between groups. CONCLUSIONS To the best of our knowledge, this study represents the initial assessment of FcRn expression in endometrioid EC samples. FcRn expression was significantly associated with the FIGO stage. Ishikawa cell line proliferation did not significantly change in response to decreased FcRn expression. Further studies are needed to elucidate FcRn expression in EC as a potential molecular parameter.
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Affiliation(s)
- Dae Hyun Song
- Department of Pathology, Gyeongsang National University School of Medicine, Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea; (D.H.S.); (M.H.K.)
- Department of Pathology, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.); (C.H.K.); (J.Y.J.)
| | - Juseok Yang
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.); (C.H.K.); (J.Y.J.)
- Department of Obstetrics and Gynecology, Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju 52727, Republic of Korea
| | - Cho Hee Kim
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.); (C.H.K.); (J.Y.J.)
| | - Min Hye Kim
- Department of Pathology, Gyeongsang National University School of Medicine, Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea; (D.H.S.); (M.H.K.)
- Department of Pathology, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.); (C.H.K.); (J.Y.J.)
| | - Jae Yoon Jo
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.); (C.H.K.); (J.Y.J.)
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju 52727, Republic of Korea
- Department of Obstetrics and Gynecology, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
| | - Jong Chul Baek
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.); (C.H.K.); (J.Y.J.)
- Department of Obstetrics and Gynecology, Gyeongsang National University Changwon Hospital, 11, Samjeongja-ro, Seongsan-gu, Changwon-si 51472, Republic of Korea
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju 52727, Republic of Korea
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18
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Abstract
IgGs are essential soluble components of the adaptive immune response that evolved to protect the body from infection. Compared with other immunoglobulins, the role of IgGs is distinguished and enhanced by their high circulating levels, long half-life and ability to transfer from mother to offspring, properties that are conferred by interactions with neonatal Fc receptor (FcRn). FcRn binds to the Fc portion of IgGs in a pH-dependent manner and protects them from intracellular degradation. It also allows their transport across polarized cells that separate tissue compartments, such as the endothelium and epithelium. Further, it is becoming apparent that FcRn functions to potentiate cellular immune responses when IgGs, bound to their antigens, form IgG immune complexes. Besides the protective role of IgG, IgG autoantibodies are associated with numerous pathological conditions. As such, FcRn blockade is a novel and effective strategy to reduce circulating levels of pathogenic IgG autoantibodies and curtail IgG-mediated diseases, with several FcRn-blocking strategies on the path to therapeutic use. Here, we describe the current state of knowledge of FcRn-IgG immunobiology, with an emphasis on the functional and pathological aspects, and an overview of FcRn-targeted therapy development.
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Affiliation(s)
- Michal Pyzik
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Lisa K Kozicky
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Amit K Gandhi
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Richard S Blumberg
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Harvard Digestive Diseases Center, Boston, MA, USA.
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19
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Banushi B, Joseph SR, Lum B, Lee JJ, Simpson F. Endocytosis in cancer and cancer therapy. Nat Rev Cancer 2023:10.1038/s41568-023-00574-6. [PMID: 37217781 DOI: 10.1038/s41568-023-00574-6] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/11/2023] [Indexed: 05/24/2023]
Abstract
Endocytosis is a complex process whereby cell surface proteins, lipids and fluid from the extracellular environment are packaged, sorted and internalized into cells. Endocytosis is also a mechanism of drug internalization into cells. There are multiple routes of endocytosis that determine the fate of molecules, from degradation in the lysosomes to recycling back to the plasma membrane. The overall rates of endocytosis and temporal regulation of molecules transiting through endocytic pathways are also intricately linked with signalling outcomes. This process relies on an array of factors, such as intrinsic amino acid motifs and post-translational modifications. Endocytosis is frequently disrupted in cancer. These disruptions lead to inappropriate retention of receptor tyrosine kinases on the tumour cell membrane, changes in the recycling of oncogenic molecules, defective signalling feedback loops and loss of cell polarity. In the past decade, endocytosis has emerged as a pivotal regulator of nutrient scavenging, response to and regulation of immune surveillance and tumour immune evasion, tumour metastasis and therapeutic drug delivery. This Review summarizes and integrates these advances into the understanding of endocytosis in cancer. The potential to regulate these pathways in the clinic to improve cancer therapy is also discussed.
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Affiliation(s)
- Blerida Banushi
- Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Shannon R Joseph
- Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Benedict Lum
- Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Jason J Lee
- Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Fiona Simpson
- Frazer Institute, University of Queensland, Woolloongabba, Queensland, Australia.
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20
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Zhu W, Wu J, Huang J, Xiao D, Li F, Wu C, Li X, Zeng H, Zheng J, Lai W, Wen X. Multi-omics analysis reveals a macrophage-related marker gene signature for prognostic prediction, immune landscape, genomic heterogeneity, and drug choices in prostate cancer. Front Immunol 2023; 14:1122670. [PMID: 37122696 PMCID: PMC10140525 DOI: 10.3389/fimmu.2023.1122670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 04/03/2023] [Indexed: 05/02/2023] Open
Abstract
INTRODUCTION Macrophages are components of the innate immune system and can play an anti-tumor or pro-tumor role in the tumor microenvironment owing to their high heterogeneity and plasticity. Meanwhile, prostate cancer (PCa) is an immune-sensitive tumor, making it essential to investigate the value of macrophage-associated networks in its prognosis and treatment. METHODS Macrophage-related marker genes (MRMGs) were identified through the comprehensive analysis of single-cell sequencing data from GSE141445 and the impact of macrophages on PCa was evaluated using consensus clustering of MRMGs in the TCGA database. Subsequently, a macrophage-related marker gene prognostic signature (MRMGPS) was constructed by LASSO-Cox regression analysis and grouped based on the median risk score. The predictive ability of MRMGPS was verified by experiments, survival analysis, and nomogram in the TCGA cohort and GEO-Merged cohort. Additionally, immune landscape, genomic heterogeneity, tumor stemness, drug sensitivity, and molecular docking were conducted to explore the relationship between MRMGPS and the tumor immune microenvironment, therapeutic response, and drug selection. RESULTS We identified 307 MRMGs and verified that macrophages had a strong influence on the development and progression of PCa. Furthermore, we showed that the MRMGPS constructed with 9 genes and the predictive nomogram had excellent predictive ability in both the TCGA and GEO-Merged cohorts. More importantly, we also found the close relationship between MRMGPS and the tumor immune microenvironment, therapeutic response, and drug selection by multi-omics analysis. DISCUSSION Our study reveals the application value of MRMGPS in predicting the prognosis of PCa patients. It also provides a novel perspective and theoretical basis for immune research and drug choices for PCa.
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Affiliation(s)
- Weian Zhu
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianjie Wu
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiongduan Huang
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dongming Xiao
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Fengao Li
- Department of Urology, Anqing First People’s Hospital of Anhui Medical University, Anqing, China
| | - Chenglun Wu
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaojuan Li
- Department of Health Care, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Hengda Zeng
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiayu Zheng
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenjie Lai
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xingqiao Wen
- Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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21
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Toshkova N, Zhelyazkova V, Justesen S, Dimitrov JD. Conservative pattern of interaction of bat and human IgG antibodies with FcRn. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 139:104579. [PMID: 36272453 DOI: 10.1016/j.dci.2022.104579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/03/2022] [Accepted: 10/17/2022] [Indexed: 06/16/2023]
Abstract
Recently, numerous studies report bats as reservoirs of emerging pathogens with little to no signs of infections. This is thought to be connected to the unique immune system of bats, which remains poorly characterized. Despite the physiological importance of the Neonatal Fc receptor (FcRn) in the homeostasis of IgG antibodies, it is unclear how its functional activity is evolutionary conservative among mammals, and so is the case for bats. Using surface plasmon resonance-based technology, we tested the interactions of IgG antibodies isolated from three bat species with recombinant human and mouse FcRn. Our data show that IgG from the studied bat species binds to both human and mouse FcRn, albeit with distinct affinities. Importantly, the binding pattern of bat IgG is similar to human IgG. This confirms the conservative nature of IgG-FcRn interaction and highlights the importance of FcRn IgG salvaging system in bats.
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Affiliation(s)
- Nia Toshkova
- National Museum of Natural History, Bulgarian Academy of Sciences, 1 Tsar Osvoboditel Blvd., 1000, Sofia, Bulgaria; Institute of Biodiversity and Ecosystem Research, Bulgarian Academy of Sciences, 1 Tsar Osvoboditel Blvd., 1000, Sofia, Bulgaria.
| | - Violeta Zhelyazkova
- National Museum of Natural History, Bulgarian Academy of Sciences, 1 Tsar Osvoboditel Blvd., 1000, Sofia, Bulgaria; Centre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, Université de Paris, 75006, Paris, France
| | - Sune Justesen
- Immunitrack Aps, Lersoe Park Alle 42, 2100, Copenhagen East, Denmark
| | - Jordan D Dimitrov
- Centre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, Université de Paris, 75006, Paris, France.
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22
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Chen X, Liu X, Jiang Y, Xia N, Liu C, Luo W. Abnormally primed CD8 T cells: The Achilles' heel of CHB. Front Immunol 2023; 14:1106700. [PMID: 36936922 PMCID: PMC10014547 DOI: 10.3389/fimmu.2023.1106700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 02/20/2023] [Indexed: 03/05/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a significant public health challenge, and more than 250 million people around world are infected with HBV. The clearance of HBV with virus-specific CD8 T cells is critical for a functional cure. However, naïve HBV-specific CD8 T cells are heavily hindered during the priming process, and this phenomenon is closely related to abnormal cell and signal interactions in the complex immune microenvironment. Here, we briefly summarize the recent progress in understanding the abnormal priming of HBV-specific CD8 T cells and some corresponding immunotherapies to facilitate their functional recovery, which provides a novel perspective for the design and development of immunotherapy for chronic HBV infection (CHB). Finally, we also highlight the balance between viral clearance and pathological liver injury induced by CD8 T-cell activation that should be carefully considered during drug development.
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Affiliation(s)
- Xiaoqing Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Xue Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Yichao Jiang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- Xiang An Biomedicine Laboratory, Xiamen, Fujian, China
- The Research Unit of Frontier Technology of Structural Vaccinology, Chinese Academy of Medical Sciences, Xiamen, Fujian, China
| | - Chao Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
- *Correspondence: Wenxin Luo, ; Chao Liu,
| | - Wenxin Luo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- Xiang An Biomedicine Laboratory, Xiamen, Fujian, China
- *Correspondence: Wenxin Luo, ; Chao Liu,
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23
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Lamamy J, Larue A, Mariot J, Dhommée C, Demattei MV, Delneste Y, Gouilleux-Gruart V. The neonatal Fc receptor expression during macrophage differentiation is related to autophagy. Front Immunol 2022; 13:1054425. [PMID: 36389739 PMCID: PMC9663809 DOI: 10.3389/fimmu.2022.1054425] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022] Open
Abstract
The neonatal Fc receptor (FcRn) plays a central role in recycling and biodistributing immunoglobulin G. FcRn is also involved in many physiological immune functions as well as pathological immune responses in cancer or autoimmune diseases. Low levels of FcRn in tumor cells and the microenvironment is associated with poor prognosis in non-small cell lung cancers. Among cells that are present in the tumor microenvironment, macrophages express high levels of FcRn. Macrophages are involved in these pathophysiological contexts by their dual differentiation states of pro- or anti-inflammatory macrophages. However, variations in FcRn protein expression have not been described in macrophage subtypes. In this work, we studied FcRn expression in an in vitro model of pro- and anti-inflammatory macrophage differentiation. We demonstrated an inverse relation between FcRn protein and mRNA expression in macrophage populations. Autophagy, which is involved in protein degradation and acquisition of phagocytic function in macrophages, participated in regulating FcRn levels. Intravenous immunoglobulin protected FcRn against autophagosome degradation in anti-inflammatory macrophages. Our data demonstrate that autophagy participates in regulating FcRn expression in pro- and anti-inflammatory macrophages. This finding raises new questions concerning the regulation of FcRn in immune functions.
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Affiliation(s)
| | | | | | | | | | - Yves Delneste
- CRCI2NA, SFR ICAT, Inserm, CNRS, Angers and Nantes University, Angers, France
- Laboratory of Immunology and Allergology, CHU d’Angers, Angers, France
| | - Valérie Gouilleux-Gruart
- EA 7501 GICC, Tours University, Tours, France
- Laboratory of Immunology, CHU de Tours, Tours, France
- *Correspondence: Valérie Gouilleux-Gruart,
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24
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Yang R, Zhang W, Shang X, Chen H, Mu X, Zhang Y, Zheng Q, Wang X, Liu Y. Neutrophil-related genes predict prognosis and response to immune checkpoint inhibitors in bladder cancer. Front Pharmacol 2022; 13:1013672. [PMID: 36339597 PMCID: PMC9635818 DOI: 10.3389/fphar.2022.1013672] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 10/12/2022] [Indexed: 12/20/2023] Open
Abstract
Neutrophils play a key role in the occurrence and development of cancer. However, the relationship between neutrophils and cancer prognosis remains unclear due to their great plasticity and diversity. To explore the effects of neutrophils on the clinical outcome of bladder cancer, we acquired and analyzed gene expression data and clinical information of bladder cancer patients from IMvigor210 cohort and The Cancer Genome Atlas dataset (TCGA) database. We established a neutrophil-based prognostic model incorporating five neutrophil-related genes (EMR3, VNN1, FCGRT, HIST1H2BC, and MX1) and the predictive value of the model was validated in both an internal and an external validation cohort. Multivariate Cox regression analysis further proved that the model remained an independent prognostic factor for overall survival and a nomogram was constructed for clinical practice. Additionally, FCGRT was identified as the key neutrophil-related gene linked to an adverse prognosis of bladder cancer. Up-regulation of FCGRT indicated activated cancer metabolism, immunosuppressive tumor environment, and dysregulated functional status of immune cells. FCGRT overexpression was also correlated with decreased expression of PD-L1 and low levels of tumor mutation burden (TMB). FCGRT predicted a poor response to immunotherapy and had a close correlation with chemotherapy sensitivity. Taken together, a novel prognostic model was developed based on the expression level of neutrophil-related genes. FCGRT served as a promising candidate biomarker for anti-cancer drug response, which may contribute to individualized prognostic prediction and may contribute to clinical decision-making.
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Affiliation(s)
- Rui Yang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, China
| | - Wengang Zhang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, China
| | - Xiaoling Shang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, China
| | - Hang Chen
- School of Basic Medical Sciences, Shandong First Medical University, Jinan, China
| | - Xin Mu
- Department of Medical Imaging Center, Third People’s Hospital of Jinan, Jinan, China
| | - Yuqing Zhang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, China
| | - Qi Zheng
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, China
| | - Xiuwen Wang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, China
| | - Yanguo Liu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, China
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25
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Heterogeneity and Functions of Tumor-Infiltrating Antibody Secreting Cells: Lessons from Breast, Ovarian, and Other Solid Cancers. Cancers (Basel) 2022; 14:cancers14194800. [PMID: 36230721 PMCID: PMC9563085 DOI: 10.3390/cancers14194800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary B cells are gaining increasing recognition as important contributors to the tumor microenvironment, influencing, positively or negatively, tumor growth, patient survival, and response to therapies. Antibody secreting cells (ASCs) constitute a variable fraction of tumor-infiltrating B cells in most solid tumors, and they produce tumor-specific antibodies that can drive distinct immune responses depending on their isotypes and specificities. In this review, we discuss the current knowledge of the heterogeneity of ASCs infiltrating solid tumors and how both their canonical and noncanonical functions shape antitumor immunity, with a special emphasis on breast and ovarian cancers. Abstract Neglected for a long time in cancer, B cells and ASCs have recently emerged as critical actors in the tumor microenvironment, with important roles in shaping the antitumor immune response. ASCs indeed exert a major influence on tumor growth, patient survival, and response to therapies. The mechanisms underlying their pro- vs. anti-tumor roles are beginning to be elucidated, revealing the contributions of their secreted antibodies as well as of their emerging noncanonical functions. Here, concentrating mostly on ovarian and breast cancers, we summarize the current knowledge on the heterogeneity of tumor-infiltrating ASCs, we discuss their possible local or systemic origin in relation to their immunoglobulin repertoire, and we review the different mechanisms by which antibody (Ab) subclasses and isoforms differentially impact tumor cells and anti-tumor immunity. We also discuss the emerging roles of cytokines and other immune modulators produced by ASCs in cancer. Finally, we propose strategies to manipulate the tumor ASC compartment to improve cancer therapies.
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26
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Cruz AR, Bentlage AEH, Blonk R, de Haas CJC, Aerts PC, Scheepmaker LM, Bouwmeester IG, Lux A, van Strijp JAG, Nimmerjahn F, van Kessel KPM, Vidarsson G, Rooijakkers SHM. Toward Understanding How Staphylococcal Protein A Inhibits IgG-Mediated Phagocytosis. THE JOURNAL OF IMMUNOLOGY 2022; 209:1146-1155. [DOI: 10.4049/jimmunol.2200080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 07/13/2022] [Indexed: 01/04/2023]
Abstract
Abstract
IgG molecules are crucial for the human immune response against bacterial infections. IgGs can trigger phagocytosis by innate immune cells, like neutrophils. To do so, IgGs should bind to the bacterial surface via their variable Fab regions and interact with Fcγ receptors and complement C1 via the constant Fc domain. C1 binding to IgG-labeled bacteria activates the complement cascade, which results in bacterial decoration with C3-derived molecules that are recognized by complement receptors on neutrophils. Next to FcγRs and complement receptors on the membrane, neutrophils also express the intracellular neonatal Fc receptor (FcRn). We previously reported that staphylococcal protein A (SpA), a key immune-evasion protein of Staphylococcus aureus, potently blocks IgG-mediated complement activation and killing of S. aureus by interfering with IgG hexamer formation. SpA is also known to block IgG-mediated phagocytosis in absence of complement, but the mechanism behind it remains unclear. In this study, we demonstrate that SpA blocks IgG-mediated phagocytosis and killing of S. aureus and that it inhibits the interaction of IgGs with FcγRs (FcγRIIa and FcγRIIIb, but not FcγRI) and FcRn. Furthermore, our data show that multiple SpA domains are needed to effectively block IgG1-mediated phagocytosis. This provides a rationale for the fact that SpA from S. aureus contains four to five repeats. Taken together, our study elucidates the molecular mechanism by which SpA blocks IgG-mediated phagocytosis and supports the idea that in addition to FcγRs, the intracellular FcRn is also prevented from binding IgG by SpA.
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Affiliation(s)
- Ana Rita Cruz
- *Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Arthur E. H. Bentlage
- †Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; and
| | - Robin Blonk
- *Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Carla J. C. de Haas
- *Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Piet C. Aerts
- *Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Lisette M. Scheepmaker
- *Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Inge G. Bouwmeester
- *Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Anja Lux
- ‡Division of Genetics, Department of Biology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Jos A. G. van Strijp
- *Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Falk Nimmerjahn
- ‡Division of Genetics, Department of Biology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Kok P. M. van Kessel
- *Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Gestur Vidarsson
- †Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; and
| | - Suzan H. M. Rooijakkers
- *Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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27
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Hameedat F, Pizarroso NA, Teixeira N, Pinto S, Sarmento B. Functionalized FcRn-targeted nanosystems for oral drug delivery: A new approach to colorectal cancer treatment. Eur J Pharm Sci 2022; 176:106259. [PMID: 35842140 DOI: 10.1016/j.ejps.2022.106259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/01/2022] [Accepted: 07/11/2022] [Indexed: 01/17/2023]
Abstract
Colorectal cancer (CRC) is the second type of cancer with the highest lethality rate. The current chemotherapy to treat CRC causes systemic toxicity, unsatisfying response rate, and low tumor-specific selectivity, which is mainly administered by invasive routes. The chronic and aggressive nature of cancers may require long-term regimens. Thus, the oral route is preferred. However, the orally administered drugs still need to surpass the harsh environment of the gastrointestinal tract and the biological barriers. Nanotechnology is a promising strategy to overcome the oral route limitations. Targeted nanoparticle systems decorated with functional groups can enhance the delivery of anticancer agents to tumor sites. It is described in the literature that the neonatal Fc receptor (FcRn) is expressed in cancer tissue and overexpressed in CRC epithelial cells. However, the impact of FcRn-targeted nanosystems in the treatment of CRC has been poorly investigated. This review article discusses the current knowledge on the involvement of the FcRn in CRC, as well as to critically assess its relevance as a target for further localization of oral nanocarriers in CRC tumor cells. Finally, a brief overview of cancer therapeutics, strategies to design the nanoparticles of anticancer drugs and a review of decorated nanoparticles with FcRn moieties are explored.
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Affiliation(s)
- Fatima Hameedat
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; NANOMED EMJMD, Pharmacy School, Faculty of Health, University of Angers, France; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal
| | - Nuria A Pizarroso
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal
| | - Natália Teixeira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, Porto 4169-007, Portugal
| | - Soraia Pinto
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Rua Jorge Viterbo Ferreira, 228, Porto 4150-180, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-393, Portugal; CESPU - IUCS, Rua Central de Gandra 1317, Gandra 4585-116, Portugal.
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Monoclonal Antibody Engineering and Design to Modulate FcRn Activities: A Comprehensive Review. Int J Mol Sci 2022; 23:ijms23179604. [PMID: 36077002 PMCID: PMC9455995 DOI: 10.3390/ijms23179604] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 01/03/2023] Open
Abstract
Understanding the biological mechanisms underlying the pH-dependent nature of FcRn binding, as well as the various factors influencing the affinity to FcRn, was concurrent with the arrival of the first recombinant IgG monoclonal antibodies (mAbs) and IgG Fc-fusion proteins in clinical practice. IgG Fc–FcRn became a central subject of interest for the development of these drugs for the comfort of patients and good clinical responses. In this review, we describe (i) mAb mutations close to and outside the FcRn binding site, increasing the affinity for FcRn at acidic pH and leading to enhanced mAb half-life and biodistribution, and (ii) mAb mutations increasing the affinity for FcRn at acidic and neutral pH, blocking FcRn binding and resulting, in vivo, in endogenous IgG degradation. Mutations modifying FcRn binding are discussed in association with pH-dependent modulation of antigen binding and (iii) anti-FcRn mAbs, two of the latest innovations in anti-FcRn mAbs leading to endogenous IgG depletion. We discuss the pharmacological effects, the biological consequences, and advantages of targeting IgG–FcRn interactions and their application in human therapeutics.
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29
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Antigen-bearing outer membrane vesicles as tumour vaccines produced in situ by ingested genetically engineered bacteria. Nat Biomed Eng 2022; 6:898-909. [PMID: 35501399 DOI: 10.1038/s41551-022-00886-2] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 03/21/2022] [Indexed: 02/05/2023]
Abstract
The complex gastrointestinal environment and the intestinal epithelial barrier constrain the design and effectiveness of orally administered tumour vaccines. Here we show that outer membrane vesicles (OMVs) fused to a tumour antigen and produced in the intestine by ingested genetically engineered bacteria function as effective tumour vaccines in mice. We modified Escherichia coli to express, under the control of a promoter induced by the monosaccharide arabinose, a specific tumour antigen fused with the protein cytolysin A on the surface of OMVs released by the commensal bacteria. In mice, oral administration of arabinose and the genetically engineered E. coli led to the production of OMVs that crossed the intestinal epithelium into the lamina propria, where they stimulated dendritic cell maturation. In a mouse model of pulmonary metastatic melanoma and in mice bearing subcutaneous colon tumours, the antigen-bearing OMVs inhibited tumour growth and protected the animals against tumour re-challenge. The in situ production of OMVs by genetically modified commensal bacteria for the delivery of stimulatory molecules could be leveraged for the development of other oral vaccines and therapeutics.
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Thomas J, Torok MA, Agrawal K, Pfau T, Vu TT, Lyberger J, Chang H, Castillo AMM, Chen M, Remaily B, Kim K, Xie Z, Dillhoff ME, Kulp SK, Behbehani GK, Cruz-Monserrate Z, Ganesan LP, Owen DH, Phelps MA, Coss CC, Mace TA. The Neonatal Fc Receptor Is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer. Int J Mol Sci 2022; 23:7066. [PMID: 35806069 PMCID: PMC9266939 DOI: 10.3390/ijms23137066] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/20/2022] [Accepted: 06/22/2022] [Indexed: 12/16/2022] Open
Abstract
The neonatal Fc receptor (FcRn) is responsible for recycling of IgG antibodies and albumin throughout the body. This mechanism has been exploited for pharmaceutic delivery across an array of diseases to either enhance or diminish this function. Monoclonal antibodies and albumin-bound nanoparticles are examples of FcRn-dependent anti-cancer therapeutics. Despite its importance in drug delivery, little is known about FcRn expression in circulating immune cells. Through time-of-flight mass cytometry (CyTOF) we were able to characterize FcRn expression in peripheral blood mononuclear cell (PBMC) populations of pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer donors. Furthermore, we were able to replicate these findings in an orthotopic murine model of PDAC. Altogether, we found that in both patients and mice with PDAC, FcRn was elevated in migratory and resident classical dendritic cell type 2 (cDC2) as well as monocytic and granulocytic myeloid-derived suppressor cell (MDSC) populations compared to tumor-free controls. Furthermore, PBMCs from PDAC patients had elevated monocyte, dendritic cells and MDSCs relative to non-cancer donor PBMCs. Future investigations into FcRn activity may further elucidate possible mechanisms of poor efficacy of antibody immunotherapies in patients with PDAC.
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Affiliation(s)
- Justin Thomas
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (J.T.); (T.T.V.); (A.M.M.C.); (M.C.); (B.R.); (K.K.); (Z.X.); (S.K.K.); (M.A.P.)
| | - Molly A. Torok
- The James Comprehensive Cancer Center, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (M.A.T.); (K.A.); (T.P.); (Z.C.-M.); (D.H.O.)
| | - Kriti Agrawal
- The James Comprehensive Cancer Center, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (M.A.T.); (K.A.); (T.P.); (Z.C.-M.); (D.H.O.)
| | - Timothy Pfau
- The James Comprehensive Cancer Center, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (M.A.T.); (K.A.); (T.P.); (Z.C.-M.); (D.H.O.)
| | - Trang T. Vu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (J.T.); (T.T.V.); (A.M.M.C.); (M.C.); (B.R.); (K.K.); (Z.X.); (S.K.K.); (M.A.P.)
| | - Justin Lyberger
- Division of Hematology, Department of Internal Medicine, The Ohio State University, 420 W. 12th Ave., Columbus, OH 43210, USA; (J.L.); (H.C.); (G.K.B.)
| | - Hsiaochi Chang
- Division of Hematology, Department of Internal Medicine, The Ohio State University, 420 W. 12th Ave., Columbus, OH 43210, USA; (J.L.); (H.C.); (G.K.B.)
| | - Alyssa Marie M. Castillo
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (J.T.); (T.T.V.); (A.M.M.C.); (M.C.); (B.R.); (K.K.); (Z.X.); (S.K.K.); (M.A.P.)
| | - Min Chen
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (J.T.); (T.T.V.); (A.M.M.C.); (M.C.); (B.R.); (K.K.); (Z.X.); (S.K.K.); (M.A.P.)
| | - Bryan Remaily
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (J.T.); (T.T.V.); (A.M.M.C.); (M.C.); (B.R.); (K.K.); (Z.X.); (S.K.K.); (M.A.P.)
| | - Kyeongmin Kim
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (J.T.); (T.T.V.); (A.M.M.C.); (M.C.); (B.R.); (K.K.); (Z.X.); (S.K.K.); (M.A.P.)
| | - Zhiliang Xie
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (J.T.); (T.T.V.); (A.M.M.C.); (M.C.); (B.R.); (K.K.); (Z.X.); (S.K.K.); (M.A.P.)
| | - Mary E. Dillhoff
- Division of Surgical Oncology, Department of Internal Medicine, The Ohio State University, 420 W. 12th Ave., Columbus, OH 43210, USA;
| | - Samuel K. Kulp
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (J.T.); (T.T.V.); (A.M.M.C.); (M.C.); (B.R.); (K.K.); (Z.X.); (S.K.K.); (M.A.P.)
| | - Gregory K. Behbehani
- Division of Hematology, Department of Internal Medicine, The Ohio State University, 420 W. 12th Ave., Columbus, OH 43210, USA; (J.L.); (H.C.); (G.K.B.)
| | - Zobeida Cruz-Monserrate
- The James Comprehensive Cancer Center, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (M.A.T.); (K.A.); (T.P.); (Z.C.-M.); (D.H.O.)
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University, 420 W. 12th Ave., Columbus, OH 43210, USA
| | - Latha P. Ganesan
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University, 420 W. 12th Ave., Columbus, OH 43210, USA;
| | - Dwight H. Owen
- The James Comprehensive Cancer Center, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (M.A.T.); (K.A.); (T.P.); (Z.C.-M.); (D.H.O.)
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, 420 W. 12th Ave., Columbus, OH 43210, USA
| | - Mitch A. Phelps
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (J.T.); (T.T.V.); (A.M.M.C.); (M.C.); (B.R.); (K.K.); (Z.X.); (S.K.K.); (M.A.P.)
- The James Comprehensive Cancer Center, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (M.A.T.); (K.A.); (T.P.); (Z.C.-M.); (D.H.O.)
| | - Christopher C. Coss
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (J.T.); (T.T.V.); (A.M.M.C.); (M.C.); (B.R.); (K.K.); (Z.X.); (S.K.K.); (M.A.P.)
- The James Comprehensive Cancer Center, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (M.A.T.); (K.A.); (T.P.); (Z.C.-M.); (D.H.O.)
| | - Thomas A. Mace
- The James Comprehensive Cancer Center, The Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA; (M.A.T.); (K.A.); (T.P.); (Z.C.-M.); (D.H.O.)
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University, 420 W. 12th Ave., Columbus, OH 43210, USA
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Fleming A, Castro‐Dopico T, Clatworthy MR. B cell class switching in intestinal immunity in health and disease. Scand J Immunol 2022; 95:e13139. [PMID: 34978077 PMCID: PMC9285483 DOI: 10.1111/sji.13139] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 12/31/2021] [Accepted: 12/31/2021] [Indexed: 12/12/2022]
Abstract
The gastrointestinal tract is colonized by trillions of commensal microorganisms that collectively form the microbiome and make essential contributions to organism homeostasis. The intestinal immune system must tolerate these beneficial commensals, whilst preventing pathogenic organisms from systemic spread. Humoral immunity plays a key role in this process, with large quantities of immunoglobulin (Ig)A secreted into the lumen on a daily basis, regulating the microbiome and preventing bacteria from encroaching on the epithelium. However, there is an increasing appreciation of the role of IgG antibodies in intestinal immunity, including beneficial effects in neonatal immune development, pathogen and tumour resistance, but also of pathological effects in driving chronic inflammation in inflammatory bowel disease (IBD). These antibody isotypes differ in effector function, with IgG exhibiting more proinflammatory capabilities compared with IgA. Therefore, the process that leads to the generation of different antibody isotypes, class-switch recombination (CSR), requires careful regulation and is orchestrated by the immunological cues generated by the prevalent local challenge. In general, an initiating signal such as CD40 ligation on B cells leads to the induction of activation-induced cytidine deaminase (AID), but a second cytokine-mediated signal determines which Ig heavy chain is expressed. Whilst the cytokines driving intestinal IgA responses are well-studied, there is less clarity on how IgG responses are generated in the intestine, and how these cues might become dysfunctional in IBD. Here, we review the key mechanisms regulating class switching to IgA vs IgG in the intestine, processes that could be therapeutically manipulated in infection and IBD.
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Affiliation(s)
- Aaron Fleming
- Molecular Immunity UnitDepartment of MedicineCambridge Institute of Therapeutic Immunology and Infectious DiseasesUniversity of CambridgeCambridgeUK
| | - Tomas Castro‐Dopico
- Molecular Immunity UnitDepartment of MedicineCambridge Institute of Therapeutic Immunology and Infectious DiseasesUniversity of CambridgeCambridgeUK
- The Francis Crick InstituteLondonUK
| | - Menna R. Clatworthy
- Molecular Immunity UnitDepartment of MedicineCambridge Institute of Therapeutic Immunology and Infectious DiseasesUniversity of CambridgeCambridgeUK
- Cellular GeneticsWellcome Trust Sanger InstituteHinxtonUK
- NIHR Cambridge Biomedical Research CentreCambridgeUK
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32
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Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction. Signal Transduct Target Ther 2022; 7:19. [PMID: 35046386 PMCID: PMC8770466 DOI: 10.1038/s41392-021-00820-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 10/05/2021] [Accepted: 10/12/2021] [Indexed: 02/05/2023] Open
Abstract
Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.
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33
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Nawab DH. Vaccinal antibodies: Fc antibody engineering to improve the antiviral antibody response and induce vaccine-like effects. Hum Vaccin Immunother 2021; 17:5532-5545. [PMID: 34844516 PMCID: PMC8903937 DOI: 10.1080/21645515.2021.1985891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 09/21/2021] [Indexed: 10/19/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic highlights the urgent clinical need for efficient virus therapies and vaccines. Although the functional importance of antibodies is indisputable in viral infections, there are still significant unmet needs that require vast improvements in antibody-based therapeutics. The IgG Fc domain can be engineered to produce antibodies with tailored and potent responses that will meet these clinical demands. Engaging Fc receptors (FcRs) to perform effector functions as cytotoxicity, phagocytosis, complement activation, intracellular neutralization and controlling antibody persistence. Furthermore, it produces vaccine-like effects by activating signals to stimulate T-cell responses, have proven to be required for protection, as neutralization alone does not off the full protection capacity of antibodies. This review highlights antiviral Fc functions and FcRs' contributions in linking innate and adaptive immunity against viral threats. Moreover, it provides the latest Fc engineering strategies to improve the safety and efficacy of human antiviral antibodies and vaccines.
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Affiliation(s)
- Dhuha H Nawab
- Pharmacy Department, Ministry of Health, Saudi Arabia
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34
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Baumrucker CR, Macrina AL, Bruckmaier RM. Colostrogenesis: Role and Mechanism of the Bovine Fc Receptor of the Neonate (FcRn). J Mammary Gland Biol Neoplasia 2021; 26:419-453. [PMID: 35080749 DOI: 10.1007/s10911-021-09506-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 12/10/2021] [Indexed: 11/28/2022] Open
Abstract
Colostrogenesis is a separate and unique phase of mammary epithelial cell activity occurring in the weeks before parturition and rather abruptly ending after birth in the bovine. It has been the focus of research to define what controls this process and how it produces high concentrations of specific biologically active components important for the neonate. In this review we consider colostrum composition and focus upon components that appear in first milked colostrum in concentrations exceeding that in blood serum. The Fc Receptor of the Neonate (FcRn) is recognized as the major immunoglobulin G (IgG) and albumin binding protein that accounts for the proteins' long half-lives. We integrate the action of the pinocytotic (fluid phase) uptake of extracellular components and merge them with FcRn in sorting endosomes. We define and explore the means of binding, sorting, and the transcytotic delivery of IgG1 while recycling IgG2 and albumin. We consider the means of releasing the ligands from the receptor within the endosome and describe a new secretion mechanism of cargo release into colostrum without the appearance of FcRn itself in colostrum. We integrate the insulin-like growth factor family, some of which are highly concentrated bioactive components of colostrum, with the mechanisms related to FcRn endosome action. In addition to secretion, we highlight the recent findings of a role of the FcRn in phagocytosis and antigen presentation and relate its significant and abrupt change in cellular location after parturition to a role in the prevention and resistance to mastitis infections.
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Affiliation(s)
- Craig R Baumrucker
- Department of Animal Science, Penn State University, University Park, PA, 16802, USA.
- Veterinary Physiology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.
| | - Ann L Macrina
- Department of Animal Science, Penn State University, University Park, PA, 16802, USA
| | - Rupert M Bruckmaier
- Veterinary Physiology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland
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35
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Yanis R, Bergua C, Christelle B, Maillot F, Bigot A, Beurier P, Ferreira-Maldent N, Diot E, Gouilleux-Gruart V. Neonatal Fc receptor expression in lymphoid and myeloid cells in systemic lupus erythematosus. Lupus 2021; 30:1938-1945. [PMID: 34634960 DOI: 10.1177/09612033211045049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The neonatal Fc receptor (FcRn) is a ubiquitously expressed protein historically involved in IgG and albumin recycling. Recent data suggest an involvement in the pathophysiology of antibody-mediated autoimmune diseases. Among them, systemic lupus erythematosus (SLE) implies clinical and biological abnormalities of innate and adaptive circulating immune cells, potentially involving newly described functions of FcRn. In this study, FcRn expression was assessed by flow cytometry in peripheral blood leukocytes of 41 SLE patients with either active or inactive disease and 32 healthy donors. FcRn expression in B cells, natural killer cells, and T cells of SLE patients was statistically lower as compared to healthy donors. Conversely, FcRn level was statistically higher in non-classical monocyte subpopulations (CD14+CD16+ monocytes) of SLE patients versus healthy donors providing an interesting perspective to further explore its role in SLE pathophysiology.
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Affiliation(s)
- Ramdani Yanis
- Groupement Innovation et Ciblage Cellulaire EA, 26928Tours University, Tours, France.,Internal Medicine Unit, 26928University Hospital of Tours, Tours, France
| | - Cécile Bergua
- Groupement Innovation et Ciblage Cellulaire EA, 26928Tours University, Tours, France
| | | | - François Maillot
- Internal Medicine Unit, 26928University Hospital of Tours, Tours, France
| | - Adrien Bigot
- Internal Medicine Unit, 26928University Hospital of Tours, Tours, France
| | - Pauline Beurier
- Internal Medicine Unit, 26928University Hospital of Tours, Tours, France
| | | | - Elisabeth Diot
- Internal Medicine Unit, 26928University Hospital of Tours, Tours, France
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Macri C, Morgan H, Villadangos JA, Mintern JD. Regulation of dendritic cell function by Fc-γ-receptors and the neonatal Fc receptor. Mol Immunol 2021; 139:193-201. [PMID: 34560415 DOI: 10.1016/j.molimm.2021.07.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 06/28/2021] [Accepted: 07/19/2021] [Indexed: 01/02/2023]
Abstract
Dendritic cells (DCs) express receptors to sense pathogens and/or tissue damage and to communicate with other immune cells. Among those receptors, Fc receptors (FcRs) are triggered by the Fc region of antibodies produced during adaptive immunity. In this review, the role of FcγR and neonatal Fc receptor (FcRn) in DC immunity will be discussed. Their expression in DC subsets and impact on antigen uptake and presentation, DC maturation and polarisation of T cell responses will be described. Lastly, we will discuss the importance of FcR-mediated DC function in the context of immunity during viral infection, inflammatory disease, cancer and immunotherapy.
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Affiliation(s)
- Christophe Macri
- Department of Biochemistry and Pharmacology, The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, Victoria, 3010, Australia
| | - Huw Morgan
- ACRF Translational Research Laboratory, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, 3050, Australia; Department of Medicine, University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia
| | - Jose A Villadangos
- Department of Biochemistry and Pharmacology, The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, Victoria, 3010, Australia; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, 3010, Australia.
| | - Justine D Mintern
- Department of Biochemistry and Pharmacology, The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Rd, Parkville, Victoria, 3010, Australia.
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Mowat C, Mosley SR, Namdar A, Schiller D, Baker K. Anti-tumor immunity in mismatch repair-deficient colorectal cancers requires type I IFN-driven CCL5 and CXCL10. J Exp Med 2021; 218:e20210108. [PMID: 34297038 PMCID: PMC8313406 DOI: 10.1084/jem.20210108] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 05/19/2021] [Accepted: 06/29/2021] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) contain abundant CD8+ tumor-infiltrating lymphocytes (TILs) responding to the abundant neoantigens from their unstable genomes. Priming of such tumor-targeted TILs first requires recruitment of CD8+ T cells into the tumors, implying that this is an essential prerequisite of successful dMMR anti-tumor immunity. We have discovered that selective recruitment and activation of systemic CD8+ T cells into dMMR CRCs strictly depend on overexpression of CCL5 and CXCL10 due to endogenous activation of cGAS/STING and type I IFN signaling by damaged DNA. TIL infiltration into orthotopic dMMR CRCs is neoantigen-independent and followed by induction of a resident memory-like phenotype key to the anti-tumor response. CCL5 and CXCL10 could be up-regulated by common chemotherapies in all CRCs, indicating that facilitating CD8+ T cell recruitment underlies their efficacy. Induction of CCL5 and CXCL10 thus represents a tractable therapeutic strategy to induce TIL recruitment into CRCs, where local priming can be maximized even in neoantigen-poor CRCs.
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Affiliation(s)
- Courtney Mowat
- Department of Oncology, University of Alberta, Edmonton, Canada
| | | | - Afshin Namdar
- Department of Oncology, University of Alberta, Edmonton, Canada
| | - Daniel Schiller
- Department of Surgery, Royal Alexandra Hospital, Edmonton, Canada
| | - Kristi Baker
- Department of Oncology, University of Alberta, Edmonton, Canada
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada
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Guan X, Wu Y, Zhang S, Liu Z, Fan Q, Fang S, Qiao S, Sun F, Liang C. Activation of FcRn Mediates a Primary Resistance Response to Sorafenib in Hepatocellular Carcinoma by Single-Cell RNA Sequencing. Front Pharmacol 2021; 12:709343. [PMID: 34421602 PMCID: PMC8379008 DOI: 10.3389/fphar.2021.709343] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/30/2021] [Indexed: 12/11/2022] Open
Abstract
Sorafenib is the first-line therapeutic option for advanced hepatocellular carcinoma (HCC). Many patients exhibit a primary resistance (PR) response after initial treatment. In previous studies, compared to acquired resistance, the mechanism of PR is unclear. The present study aimed to evaluate the response of patient samples to sorafenib by patient-derived xenograft (PDX) models, and the differences at the transcriptome level between the sorafenib PR group and the sorafenib sensitive group were analyzed by single-cell sequencing technology. A specific cell cluster may be differentiated by the liver bud hepatic cells, and the JUN transcription factors in this cell cluster were highly activated. The albumin is secreted by other cell clusters, and the cluster stimulates the FcRn complex receptor to activate the HIF pathway and cell proliferation, resulting in a poor response to sorafenib. These findings are validated by both cell communication analysis and experiments. Thus, the current studies provided a novel approach for the treatment of sorafenib-resistant HCC.
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Affiliation(s)
| | - Yi Wu
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | | | | | | | | | | | | | - Chongyang Liang
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
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39
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Rudnik-Jansen I, Howard KA. FcRn expression in cancer: Mechanistic basis and therapeutic opportunities. J Control Release 2021; 337:248-257. [PMID: 34245786 DOI: 10.1016/j.jconrel.2021.07.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 01/30/2023]
Abstract
There is an urgent need to identify new cellular targets to expand the repertoire, potency and safety of cancer therapeutics. Neonatal Fc Receptor (FcRn)-driven cellular recycling plays a predominant role in the prolonged serum half-life of human serum albumin (HSA) and immunoglobulin G (IgG) exploited in long-acting cancer drug designs. FcRn-mediated HSA and IgG uptake in epithelial cells and dendritic cell antigen presentation offers new therapeutic opportunities beyond half-life extension. Altered FcRn expression in solid tumours accounting for HSA catabolism or recycling supports a role for FcRn in tumour metabolism and growth. This review addresses the mechanistic basis for different FcRn expression profiles observed in cancer and exploitation for targeted drug delivery. Furthermore, the review highlights FcRn-mediated immunosurveillance and immune therapy. FcRn offers a potential attractive cancer target but in-depth understanding of role and expression profiles during cancer pathogenesis is required for tailoring targeted drug designs.
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Affiliation(s)
- Imke Rudnik-Jansen
- Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark
| | - Kenneth A Howard
- Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
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40
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Sun Y, Estevez A, Schlothauer T, Wecksler AT. Antigen physiochemical properties allosterically effect the IgG Fc-region and Fc neonatal receptor affinity. MAbs 2021; 12:1802135. [PMID: 32795110 PMCID: PMC7531492 DOI: 10.1080/19420862.2020.1802135] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The neonatal Fc receptor (FcRn) is a key membrane protein that plays an integral role in serum immunoglobulin (IgG) recycling, which extends the half-life of antibody. In addition, FcRn is known to traffic antigen-bound immunoglobulins (Ag-IgGs), and to interact with immune complexes to facilitate the antigen cross-presentation of peptides derived from the immune complexes in antigen-presenting cells (APCs). Studies on the IgG-FcRn molecular interactions have primarily focused on the Fc region, and only recently have shown the potential impact of the antigen-binding fragment physiochemical properties on FcRn binding. However, the effect of the antigen physiochemical properties on IgG structure as it relates to Ag-IgG-FcRn binding is not well understood. Here we used an IgG-peptide antigen complex as a model system to investigate the structural effects of the antigen's physiochemical properties on the IgG structure, and the subsequent effects of Ag-IgG-FcRn interactions. We used hydroxyl radical footprinting-mass spectrometry to investigate the structural impact on an IgG upon antigen binding, and observed that the physicochemical properties of the antigen differentially induce conformational changes in the IgG FcRn binding region. The extent of these structural changes directly correlates to the magnitude of the affinity differences between the Ag-IgG complexes and FcRn. Moreover, the antigen's physicochemical properties differentially induce structural differences within the Ag-IgG-FcRn ternary complex. We also provide electron microscopy data that shows corroborating Fab-FcRn interactions, and confirms the hypothesis of potential 2:1 FcRn:IgG binding stoichiometry. These data demonstrate antigen-induced Fc structural rearrangements affect both the affinity toward FcRn and the trimeric antigen-IgG-FcRn complex, providing novel molecular insights in the first steps toward understanding interactions of FcRn-containing large(r)-sized immune complex.
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Affiliation(s)
- Yue Sun
- Protein Analytical Chemistry, Genentech Inc ., South San Francisco, CA, USA
| | - Alberto Estevez
- Structural Biology, Genentech Inc ., South San Francisco, CA, USA
| | - Tilman Schlothauer
- Roche Pharma Research & Early Development, Roche Innovation Center Munich , Penzberg, Germany.,Biological Technologies, Genentech Inc ., South San Francisco, CA, USA
| | - Aaron T Wecksler
- Protein Analytical Chemistry, Genentech Inc ., South San Francisco, CA, USA
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41
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Castillo AMM, Vu TT, Liva SG, Chen M, Xie Z, Thomas J, Remaily B, Guo Y, Subrayan UL, Costa T, Helms TH, Irby DJ, Kim K, Owen DH, Kulp SK, Mace TA, Phelps MA, Coss CC. Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans. JCSM RAPID COMMUNICATIONS 2021; 4:232-244. [PMID: 34514376 PMCID: PMC8420755 DOI: 10.1002/rco2.32] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 11/25/2020] [Accepted: 01/15/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have dramatically impacted oncology this past decade. However, only about one-third of patients respond to treatment, and biomarkers to predict responders are lacking. Recent ICI clinical pharmacology data demonstrate high baseline drug clearance (CL0) significantly associates with shorter overall survival, independent of ICI exposure, in patients receiving ICI mAb therapies. This suggests CL0 may predict outcomes from ICI therapy, and cachectic signalling may link elevated CL0 and poor response. Our aim was to determine if mouse models of cancer cachexia will be useful for studying these phenomena and their underlying mechanisms. METHODS We evaluated pembrolizumab CL in the C26 and Lewis lung carcinoma mouse models of cancer cachexia. A single treatment of vehicle or pembrolizumab, at a dose of 2 or 10 mg/kg, was administered intravenously by tail vein injection. Pembrolizumab was quantified by an ELISA in serial plasma samples, and FcRn gene (Fcgrt) expression was assessed in liver using real-time quantitative reverse transcription PCR. Non-compartmental and mixed-effects pharmacokinetics analyses were performed. RESULTS We observed higher pembrolizumab CL0 and decreased Fcgrt expression in whole liver tissue from tumour-bearing vs. tumour-free mice. In multivariate analysis, presence of tumour, total murine IgG, muscle weight and Fcgrt expression were significant covariates on CL, and total murine IgG was a significant covariate on V1 and Q. CONCLUSIONS These data demonstrate increases in catabolic clearance of monoclonal antibodies observed in humans can be replicated in cachectic mice, in which Fcgrt expression is also reduced. Notably, FcRn activity is essential for proper antigen presentation and antitumour immunity, which may permit the study of cachexia's impact on FcRn-mediated clearance and efficacy of ICI therapies.
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Affiliation(s)
- Alyssa Marie M. Castillo
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Trang T. Vu
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Sophia G. Liva
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Min Chen
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Zhiliang Xie
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Justin Thomas
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Bryan Remaily
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Yizhen Guo
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Uma L. Subrayan
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Travis Costa
- Department of Biomedical Engineering, College of EngineeringThe Ohio State UniversityColumbusOHUSA
| | - Timothy H. Helms
- Department of Veterinary Biosciences, College of Veterinary MedicineThe Ohio State UniversityColumbusOHUSA
| | - Donald J. Irby
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Kyeongmin Kim
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Dwight H. Owen
- Division of Medical OncologyThe Ohio State University James Comprehensive Cancer CenterColumbusOHUSA
| | - Samuel K. Kulp
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
| | - Thomas A. Mace
- Division of Gastroenterology, Hepatology & Nutrition, Department of MedicineThe Ohio State UniversityColumbusOHUSA
- The Comprehensive Cancer CenterThe Ohio State UniversityColumbusOH43210USA
| | - Mitch A. Phelps
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
- The Comprehensive Cancer CenterThe Ohio State UniversityColumbusOH43210USA
| | - Christopher C. Coss
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOHUSA
- The Comprehensive Cancer CenterThe Ohio State UniversityColumbusOH43210USA
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42
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Qi T, Cao Y. In Translation: FcRn across the Therapeutic Spectrum. Int J Mol Sci 2021; 22:3048. [PMID: 33802650 PMCID: PMC8002405 DOI: 10.3390/ijms22063048] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/11/2021] [Accepted: 03/15/2021] [Indexed: 12/14/2022] Open
Abstract
As an essential modulator of IgG disposition, the neonatal Fc receptor (FcRn) governs the pharmacokinetics and functions many therapeutic modalities. In this review, we thoroughly reexamine the hitherto elucidated biological and thermodynamic properties of FcRn to provide context for our assessment of more recent advances, which covers antigen-binding fragment (Fab) determinants of FcRn affinity, transgenic preclinical models, and FcRn targeting as an immune-complex (IC)-clearing strategy. We further comment on therapeutic antibodies authorized for treating SARS-CoV-2 (bamlanivimab, casirivimab, and imdevimab) and evaluate their potential to saturate FcRn-mediated recycling. Finally, we discuss modeling and simulation studies that probe the quantitative relationship between in vivo IgG persistence and in vitro FcRn binding, emphasizing the importance of endosomal transit parameters.
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Affiliation(s)
| | - Yanguang Cao
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA;
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43
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Shen T, Liu JL, Wang CY, Rixiati Y, Li S, Cai LD, Zhao YY, Li JM. Targeting Erbin in B cells for therapy of lung metastasis of colorectal cancer. Signal Transduct Target Ther 2021; 6:115. [PMID: 33707428 PMCID: PMC7952714 DOI: 10.1038/s41392-021-00501-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 12/15/2020] [Accepted: 01/13/2021] [Indexed: 02/07/2023] Open
Abstract
The mechanisms and key factors involved in tumor environments for lung metastasis of CRC are still unclear. Here, using clinical samples from lung metastases of CRC patients, we found that intestinal immune network for IgA production was significantly dysregulated in lung metastases of CRC. Single-cell RNA sequencing discovered a subtype of B cells positive for Erbin, one member of the leucine-rich repeat and PDZ domain (LAP) family, was involved in the lung metastases. Erbin deletion in B cells suppressed lung metastasis of CRC in vivo. And, deletion of Erbin in B cells enhanced the killing effects of CD8+ T cells on tumor cells. Mechanistically, Erbin knockout attenuated TGFβ-mediated suppression of migration of CXCR5+ IgA+ cells and STAT6-mediated PD1 expression. Our study uncovered a key role of Erbin in regulating PD1+ IgA+ B cells in lung metastasis of CRC. Targeting Erbin as well as combined use of neutralizing B cells and antibodies neutralizing PD1 suppresses lung metastasis of CRC in mice, suggesting the potential option for treatment of lung metastasis of CRC.
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Affiliation(s)
- Tong Shen
- Department of Pathology, Soochow University Medical School, Suzhou, China
| | - Jing-Lin Liu
- Department of Pathology, Soochow University Medical School, Suzhou, China
| | - Chu-Yi Wang
- Department of Pathology, Soochow University Medical School, Suzhou, China
| | | | - Shi Li
- Department of Pathology, Soochow University Medical School, Suzhou, China.,Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ling-Dong Cai
- Department of Pathology, Soochow University Medical School, Suzhou, China
| | - Yuan-Yuan Zhao
- Department of Pathology, Soochow University Medical School, Suzhou, China
| | - Jian-Ming Li
- Department of Pathology, Soochow University Medical School, Suzhou, China. .,Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
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44
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Tissues: the unexplored frontier of antibody mediated immunity. Curr Opin Virol 2021; 47:52-67. [PMID: 33581646 DOI: 10.1016/j.coviro.2021.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 01/01/2021] [Accepted: 01/05/2021] [Indexed: 12/14/2022]
Abstract
Pathogen-specific immunity evolves in the context of the infected tissue. However, current immune correlates analyses and vaccine efficacy metrics are based on immune functions from peripheral cells. Less is known about tissue-resident mechanisms of immunity. While antibodies represent the primary correlate of immunity following most clinically approved vaccines, how antibodies interact with localized, compartment-specific immune functions to fight infections, remains unclear. Emerging data demonstrate a unique community of immune cells that reside within different tissues. These tissue-specific immunological communities enable antibodies to direct both expected and unexpected local attack strategies to control, disrupt, and eliminate infection in a tissue-specific manner. Defining the full breadth of antibody effector functions, how they selectively contribute to control at the site of infection may provide clues for the design of next-generation vaccines able to direct the control, elimination, and prevention of compartment specific diseases of both infectious and non-infectious etiologies.
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45
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FcRn augments induction of tissue factor activity by IgG-containing immune complexes. Blood 2021; 135:2085-2093. [PMID: 32187355 DOI: 10.1182/blood.2019001133] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 03/03/2020] [Indexed: 12/17/2022] Open
Abstract
Thromboembolism complicates disorders caused by immunoglobulin G (IgG)-containing immune complexes (ICs), but the underlying mechanisms are incompletely understood. Prior evidence indicates that induction of tissue factor (TF) on monocytes, a pivotal step in the initiation, localization, and propagation of coagulation by ICs, is mediated through Fcγ receptor IIa (FcγRIIa); however, the involvement of other receptors has not been investigated in detail. The neonatal Fc receptor (FcRn) that mediates IgG and albumin recycling also participates in cellular responses to IgG-containing ICs. Here we asked whether FcRn is also involved in the induction of TF-dependent factor Xa (FXa) activity by IgG-containing ICs by THP-1 monocytic cells and human monocytes. Induction of FXa activity by ICs containing IgG antibodies to platelet factor 4 (PF4) involved in heparin-induced thrombocytopenia (HIT), β-2-glycoprotein-1 implicated in antiphospholipid syndrome, or red blood cells coated with anti-(α)-Rh(D) antibodies that mediate hemolysis in vivo was inhibited by a humanized monoclonal antibody (mAb) that blocks IgG binding to human FcRn. IgG-containing ICs that bind to FcγR and FcRn induced FXa activity, whereas IgG-containing ICs with an Fc engineered to be unable to engage FcRn did not. Infusion of an α-FcRn mAb prevented fibrin deposition after microvascular injury in a murine model of HIT in which human FcγRIIa was expressed as a transgene. These data implicate FcRn in TF-dependent FXa activity induced by soluble and cell-associated IgG-containing ICs. Antibodies to FcRn, now in clinical trials in warm autoimmune hemolytic anemia to lower IgG antibodies and IgG containing ICs may also reduce the risk of venous thromboembolism.
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46
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Abstract
The opposing roles of innate and adaptive immune cells in suppressing or supporting cancer initiation, progression, metastasis and response to therapy has been long debated. The mechanisms by which different monocyte and T cell subtypes affect and modulate cancer have been extensively studied. However, the role of B cells and their subtypes have remained elusive, perhaps partially due to their heterogeneity and range of actions. B cells can produce a variety of cytokines and present tumor-derived antigens to T cells in combination with co-stimulatory or inhibitory ligands based on their phenotype. Unlike most T cells, B cells can be activated by innate immune stimuli, such as endotoxin. Furthermore, the isotype and specificity of the antibodies produced by plasma cells regulate distinct immune responses, including opsonization, antibody-mediated cellular cytotoxicity (ADCC) and complement activation. B cells are shaped by the tumor environment (TME), with the capability to regulate the TME in return. In this review, we will describe the mechanisms of B cell action, including cytokine production, antigen presentation, ADCC, opsonization, complement activation and how they affect tumor development and response to immunotherapy. We will also discuss how B cell fate within the TME is affected by tumor stroma, microbiome and metabolism.
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Affiliation(s)
- Shabnam Shalapour
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Michael Karin
- Department of Pharmacology, School of Medicine, University of California San Diego, CA 92093, USA; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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47
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Nabeshima Y, Kataoka TR, Ueshima C, Saito N, Hirata M, Takeuchi Y, Takei Y, Moriyoshi K, Ono K, Haga H. Neonatal Fc receptor induces intravenous immunoglobulin growth suppression in Langerhans cell histiocytosis. Pathol Int 2021; 71:191-198. [PMID: 33497038 PMCID: PMC7986110 DOI: 10.1111/pin.13068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/26/2020] [Indexed: 11/27/2022]
Abstract
The neonatal Fc receptor (FcRn) plays a role in trafficking IgG and albumin and is thought to mediate intravenous immunoglobulin (IVIG) therapy for certain diseases. IVIG can be used for the treatment of human Langerhans cell histiocytosis (LCH); however, the mechanism remains unclear. The expression and function of FcRn protein have not been studied in LCH, though the expression of FcRn messenger RNA (mRNA) have been reported. In this report, we confirmed the expression of FcRn in 26 of 30 pathological cases (86.7%) diagnosed immunohistochemically as LCH. The expression was independent of age, gender, location, multi‐ or single‐system, and the status of BRAFV600E immunostaining. We also confirmed the expression of FcRn mRNA and protein in the human LCH‐like cell line, ELD‐1. FcRn suppressed albumin consumption and growth of IVIG preparation‐treated ELD‐1 cells, but not of IVIG preparation‐untreated or FcRn‐knockdown ELD‐1 cells. In addition, FITC‐conjugated albumin was taken into Rab11‐positive recycle vesicles in mock ELD‐1 cells but not in FcRn‐knockdown ELD‐1 cells. IVIG preparation prolonged this status in mock ELD‐1 cells. Therefore, ELD‐1 recycled albumin via FcRn and albumin was not used for metabolism. Our results increase our understanding of the molecular mechanism of IVIG treatment of LCH.
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Affiliation(s)
- Yuka Nabeshima
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Tatsuki R Kataoka
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.,Department of Molecular Diagnostic Pathology, Iwate Medical University, Iwate, Japan
| | - Chiyuki Ueshima
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Narumi Saito
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Masahiro Hirata
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Yasuhide Takeuchi
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.,Clinical Bio Resource Center, Kyoto University Hospital, Kyoto, Japan
| | - Yusuke Takei
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.,Department of Diagnostic Pathology, Saiseikai Noe Hospital, Osaka, Japan
| | - Koki Moriyoshi
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.,Department of Diagnostic Pathology, Kyoto Medical Center, Kyoto, Japan
| | - Kazuo Ono
- Department of Pathology, Japan Red Cross Society Wakayama Medical Center, Wakayama, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
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48
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Aaen KH, Anthi AK, Sandlie I, Nilsen J, Mester S, Andersen JT. The neonatal Fc receptor in mucosal immune regulation. Scand J Immunol 2021; 93:e13017. [PMID: 33351196 DOI: 10.1111/sji.13017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 11/11/2020] [Accepted: 12/21/2020] [Indexed: 01/01/2023]
Abstract
The neonatal Fc receptor (FcRn) was first recognized for its role in transfer of maternal IgG to the foetus or newborn, providing passive immunity early in life. However, it has become clear that the receptor is versatile, widely expressed and plays an indispensable role in both immunological and non-immunological processes throughout life. The receptor rescues immunoglobulin G (IgG) and albumin from intracellular degradation and shuttles the ligands across polarized cell barriers, in all cases via a pH-dependent binding-and-release mechanism. These processes secure distribution and high levels of both IgG and albumin throughout the body. At mucosal sites, FcRn transports IgG across polarized epithelial cells where it retrieves IgG in complex with luminal antigens that is delivered to tissue-localized immune cells. In dendritic cells (DCs), FcRn orchestrates processing of IgG-opsonized immune complexes (ICs) in concert with classical Fcγ receptors, which results in antigen presentation and cross-presentation of antigenic peptides on MHC class II and I to CD4+ and CD8+ T cells, respectively. Hence, FcRn regulates transport of the ligands within and across different types of cells, but also processing of IgG-ICs by immune cells. As such, the receptor is involved in immune surveillance and protection against infections. In this brief review, we highlight how FcRn expressed by hematopoietic and non-hematopoietic cells contributes to immune regulation at mucosal barriers-biology that can be utilized in development of biologics and subunit vaccines for non-invasive delivery.
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Affiliation(s)
- Kristin Hovden Aaen
- Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.,Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Aina Karen Anthi
- Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.,Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Inger Sandlie
- Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.,Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Biosciences, University of Oslo, Oslo, Norway
| | - Jeannette Nilsen
- Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.,Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Simone Mester
- Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.,Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jan Terje Andersen
- Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.,Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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49
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Castro-Dopico T, Colombel JF, Mehandru S. Targeting B cells for inflammatory bowel disease treatment: back to the future. Curr Opin Pharmacol 2020; 55:90-98. [PMID: 33166872 PMCID: PMC7894973 DOI: 10.1016/j.coph.2020.10.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/30/2020] [Accepted: 10/05/2020] [Indexed: 02/08/2023]
Abstract
B cells are critical to immune homeostasis at mucosal surfaces including those of the gastrointestinal tract. B cell-related abnormalities, comprising of a lympho-plasmacytic infiltrate, as well as anti-microbial antibodies, are well reported in patients with inflammatory bowel disease (IBD). However, B cell-targeting is not part of the therapeutic armamentarium in IBD. Recently, driven by the identification of genetic associations between IgG Fc receptors and IBD susceptibility, there has been renewed interest in defining the immunobiology of B cells during mucosal inflammation. Functional studies have demonstrated mechanisms of IgG-mediated disease pathogenesis and deep mucosal immunophenotyping using single cell RNA sequencing has elaborated a significant remodelling of the B cell compartment in IBD. In light of these novel data, here we discuss potential strategies to target B cell immunity in IBD. Finally, we discuss potential risks and pitfalls of these approaches and emphasize on distinguishing between homeostatic and pathological B cell signatures, allowing for a data-based, prudent therapeutic approach.
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Affiliation(s)
- Tomas Castro-Dopico
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Saurabh Mehandru
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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50
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Extensive variability in the composition of immune infiltrate in different mouse models of cancer. Lab Anim Res 2020; 36:43. [PMID: 33292783 PMCID: PMC7678281 DOI: 10.1186/s42826-020-00075-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 11/03/2020] [Indexed: 11/10/2022] Open
Abstract
Mouse models are invaluable tools for cancer immunology research. However, there are differences in the immune response to the tumour depending on the model used, and these differences are not often characterised on their own. Instead they are often only analysed in response to a therapeutic immune modulation. There are important issues with translatability into effective clinical research when considering the choice of mouse models. Here we analysed the tumour immune microenvironment and modified aspects of the tumour model to determine the effect on the composition of the immune infiltrate. Mice injected subcutaneously with the melanoma cell line, B16-OVA, had a higher frequency of T cells, especially CD8+ T cells, than mice injected subcutaneously with CT26 colorectal adenocarcinoma cells. We compared the same tumour cell line (CT26) delivered either subcutaneously and intracaecally. To minimise immunological impacts due to the invasive surgery procedure, we optimised an existing intracaecal injection protocol. Intracaecal tumours had a higher frequency of infiltrating CD3+ CD4+ T cells and a lower frequency of CD3-CD19- (putative NK cells) than subcutaneous tumours. In contrast, there was a higher frequency of F480+ macrophages in subcutaneous tumours than intracaecal tumours. These data demonstrate that variability between animals, between experiments and within tumour models, can lead to difficulty in interpreting the infiltrating immune response and translating this response to clinical research.
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