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He Y, Wang D, Zhang C, Huang S, Li X, Chen Y, Ma Y, Ju S, Ye H, Fan W. EGFR-targeting oxygen-saturated nanophotosensitizers for orchestrating multifaceted antitumor responses by counteracting immunosuppressive milieu. J Control Release 2024; 375:127-141. [PMID: 39233281 DOI: 10.1016/j.jconrel.2024.08.051] [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: 06/01/2024] [Revised: 08/28/2024] [Accepted: 08/30/2024] [Indexed: 09/06/2024]
Abstract
High Epidermal growth factor receptor (EGFR) in Cutaneous Squamous Cell Carcinoma (cSCC) is associated with poor prognosis and advanced metastatic stages, severely impeding the efficacy of EGFR-targeting immunotherapy. This is commonly attributed to the combinatory outcomes of hypoxic tumor microenvironment (TME) and immunosuppressive effector cells together. Herein, a novel paradigm of EGFR-targeting oxygen-saturated nanophotosensitizers, designated as CHPFN-O2, has been specifically tailored to mitigate tumor hypoxia in EGFR-positive cSCC and achieve Cetuximab (CTX)-mediated immunotherapy (CIT). The conjugated CTX in CHPFN-O2 serves to initiate immune responses by recruiting Fc receptor (FcR)-expressing immune effector cells towards tumor cells, thereby eliciting antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular trogocytosis (ADCT) and antibody-dependent cellular cytotoxicity (ADCC). Besides, CHPFN-O2 can engender a shift from a tumor-friendly to a tumor-hostile one through improved tumor oxygenation, contributing to oxygen-elevated photodynamic therapy (oxPDT). Notably, the combination of oxPDT and CIT eventually promotes T-cell-mediated antitumor activity and successfully inhibits the growth of EGFR-expressing cSCC with good safety profiles. This comprehensive oxPDT/CIT integration aims not only to enhance therapeutic efficacy against EGFRhigh cSCC but also to extend its applicability to other EGFRhigh malignancies, thus delineating a new avenue for the highly efficient synergistic treatment of EGFR-expressing malignancies.
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Affiliation(s)
- Yuan He
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Deng Wang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Cheng Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 211198, China
| | - Siting Huang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Xiangzheng Li
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yue Chen
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 211198, China
| | - Yuanyuan Ma
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Shenghong Ju
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Hongxun Ye
- Department of Radiology, Taixing People's Hospital, Medical School, Yangzhou University, Taixing 225400, China.
| | - Wenpei Fan
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 211198, China.
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Mattei F, Andreone S, Spadaro F, Noto F, Tinari A, Falchi M, Piconese S, Afferni C, Schiavoni G. Trogocytosis in innate immunity to cancer is an intimate relationship with unexpected outcomes. iScience 2022; 25:105110. [PMID: 36185368 PMCID: PMC9515589 DOI: 10.1016/j.isci.2022.105110] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 08/04/2022] [Accepted: 09/07/2022] [Indexed: 11/29/2022] Open
Abstract
Trogocytosis is a cellular process whereby a cell acquires a membrane fragment from a donor cell in a contact-dependent manner allowing for the transfer of surface proteins with functional integrity. It is involved in various biological processes, including cell-cell communication, immune regulation, and response to pathogens and cancer cells, with poorly defined molecular mechanisms. With the exception of eosinophils, trogocytosis has been reported in most immune cells and plays diverse roles in the modulation of anti-tumor immune responses. Here, we report that eosinophils acquire membrane fragments from tumor cells early after contact through the CD11b/CD18 integrin complex. We discuss the impact of trogocytosis in innate immune cells on cancer progression in the context of the evidence that eosinophils can engage in trogocytosis with tumor cells. We also discuss shared and cell-specific mechanisms underlying this process based on in silico modeling and provide a hypothetical molecular model for the stabilization of the immunological synapse operating in granulocytes and possibly other innate immune cells that enables trogocytosis.
Trogocytosis in innate immune cells can regulate immune responses to cancer Eosinophils engage in trogocytosis with tumor cells via CD11b/CD18 integrin complex CD11b/CD18 integrin, focal adhesion molecules and actin network enable trogocytosis
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Affiliation(s)
- Fabrizio Mattei
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Sara Andreone
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Francesca Spadaro
- Core Facilities, Microscopy Unit, Istituto Superiore di Sanità, Rome, Italy
| | - Francesco Noto
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Antonella Tinari
- Center for Gender Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Mario Falchi
- National HIV/AIDS Research Center (CNAIDS), Istituto Superiore di Sanità, Rome, Italy
| | - Silvia Piconese
- Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Italy
- Neuroimmunology Unit, IRCCS Fondazione Santa Lucia, Rome, Italy
- Laboratory Affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy
| | - Claudia Afferni
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Giovanna Schiavoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
- Corresponding author
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3
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Zhao S, Zhang L, Xiang S, Hu Y, Wu Z, Shen J. Gnawing Between Cells and Cells in the Immune System: Friend or Foe? A Review of Trogocytosis. Front Immunol 2022; 13:791006. [PMID: 35185886 PMCID: PMC8850298 DOI: 10.3389/fimmu.2022.791006] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 01/14/2022] [Indexed: 12/27/2022] Open
Abstract
Trogocytosis occurs when one cell contacts and quickly nibbles another cell and is characterized by contact between living cells and rapid transfer of membrane fragments with functional integrity. Many immune cells are involved in this process, such as T cells, B cells, NK cells, APCs. The transferred membrane molecules including MHC molecules, costimulatory molecules, receptors, antigens, etc. An increasing number of studies have shown that trogocytosis plays an important role in the immune system and the occurrence of relevant diseases. Thus, whether trogocytosis is a friend or foe of the immune system is puzzling, and the precise mechanism underlying it has not yet been fully elucidated. Here, we provide an integrated view of the acquired findings on the connections between trogocytosis and the immune system.
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Affiliation(s)
- Siyu Zhao
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Lichao Zhang
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Suoyu Xiang
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Yunyi Hu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Zhongdao Wu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Jia Shen
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
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4
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Trogocytosis between Non-Immune Cells for Cell Clearance, and among Immune-Related Cells for Modulating Immune Responses and Autoimmunity. Int J Mol Sci 2021; 22:ijms22052236. [PMID: 33668117 PMCID: PMC7956485 DOI: 10.3390/ijms22052236] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/21/2021] [Accepted: 02/21/2021] [Indexed: 12/21/2022] Open
Abstract
The term trogocytosis refers to a rapid bidirectional and active transfer of surface membrane fragment and associated proteins between cells. The trogocytosis requires cell-cell contact, and exhibits fast kinetics and the limited lifetime of the transferred molecules on the surface of the acceptor cells. The biological actions of trogocytosis include information exchange, cell clearance of unwanted tissues in embryonic development, immunoregulation, cancer surveillance/evasion, allogeneic cell survival and infectious pathogen killing or intercellular transmission. In the present review, we will extensively review all these aspects. In addition to its biological significance, aberrant trogocytosis in the immune system leading to autoimmunity and immune-mediated inflammatory diseases will also be discussed. Finally, the prospective investigations for further understanding the molecular basis of trogocytosis and its clinical applications will also be proposed.
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Li KJ, Wu CH, Shen CY, Kuo YM, Yu CL, Hsieh SC. Membrane Transfer from Mononuclear Cells to Polymorphonuclear Neutrophils Transduces Cell Survival and Activation Signals in the Recipient Cells via Anti-Extrinsic Apoptotic and MAP Kinase Signaling Pathways. PLoS One 2016; 11:e0156262. [PMID: 27258015 PMCID: PMC4892539 DOI: 10.1371/journal.pone.0156262] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 05/11/2016] [Indexed: 12/11/2022] Open
Abstract
The biological significance of membrane transfer (trogocytosis) between polymorphonuclear neutrophils (PMNs) and mononuclear cells (MNCs) remains unclear. We investigated the biological/immunological effects and molecular basis of trogocytosis among various immune cells in healthy individuals and patients with active systemic lupus erythematosus (SLE). By flow cytometry, we determined that molecules in the immunological synapse, including HLA class-I and-II, CD11b and LFA-1, along with CXCR1, are exchanged among autologous PMNs, CD4+ T cells, and U937 cells (monocytes) after cell-cell contact. Small interfering RNA knockdown of the integrin adhesion molecule CD11a in U937 unexpectedly enhanced the level of total membrane transfer from U937 to PMN cells. Functionally, phagocytosis and IL-8 production by PMNs were enhanced after co-culture with T cells. Total membrane transfer from CD4+ T to PMNs delayed PMN apoptosis by suppressing the extrinsic apoptotic molecules, BAX, MYC and caspase 8. This enhancement of activities of PMNs by T cells was found to be mediated via p38- and P44/42-Akt-MAP kinase pathways and inhibited by the actin-polymerization inhibitor, latrunculin B, the clathrin inhibitor, Pitstop-2, and human immunoglobulin G, but not by the caveolin inhibitor, methyl-β-cyclodextrin. In addition, membrane transfer from PMNs enhanced IL-2 production by recipient anti-CD3/anti-CD28 activated MNCs, and this was suppressed by inhibitors of mitogen-activated protein kinase (PD98059) and protein kinase C (Rottlerin). Of clinical significance, decreased total membrane transfer from PMNs to MNCs in patients with active SLE suppressed mononuclear IL-2 production. In conclusion, membrane transfer from MNCs to PMNs, mainly at the immunological synapse, transduces survival and activation signals to enhance PMN functions and is dependent on actin polymerization, clathrin activation, and Fcγ receptors, while membrane transfer from PMNs to MNCs depends on MAP kinase and PKC signaling. Defective membrane transfer from PMNs to MNCs in patients with active systemic lupus erythematous suppressed activated mononuclear IL-2 production.
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Affiliation(s)
- Ko-Jen Li
- Institute of Clinical Medicine, National Yang-Ming University College of Medicine, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Han Wu
- Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chieh-Yu Shen
- Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Min Kuo
- Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Li Yu
- Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Song-Chou Hsieh
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- * E-mail:
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Kloc M, Kubiak JZ, Li XC, Ghobrial RM. Noncanonical intercellular communication in immune response. World J Immunol 2016; 6:67-74. [DOI: 10.5411/wji.v6.i1.67] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 11/06/2015] [Accepted: 12/18/2015] [Indexed: 02/05/2023] Open
Abstract
The classical view of signaling between cells of immune system includes two major routes of intercellular communication: Through the release of extracellular molecules or a direct interaction between membrane bound receptor and its membrane bound ligand, which initiate a cascade of signaling in target cell. However, recent studies indicate that besides these canonical modes of signaling there are also noncanonical routs of intercellular communications through membrane stripping/membrane exchange/trogocytosis, extracellular traps, exosomes and ectososmes/microparticles. In this review we discuss what are the components of noncanonical pathways of signaling and what role they play in immune cells interactions.
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Fcγ-receptor-mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments. Blood 2014; 125:762-6. [PMID: 25498911 DOI: 10.1182/blood-2014-10-569244] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
A specialized form of trogocytosis occurs when Fcγ receptors on acceptor cells take up and internalize donor cell-associated immune complexes composed of specific monoclonal antibodies (mAbs) bound to target antigens on donor cells. This trogocytosis reaction, an example of antigenic modulation, has been described in recent clinical correlative studies and in vitro investigations for several mAbs used in cancer immunotherapy, including rituximab and ofatumumab. We discuss the impact of Fcγ-receptor-mediated trogocytosis on the efficacy of cancer immunotherapy and other mAb-based therapies.
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Taylor RP, Lindorfer MA. Analyses of CD20 monoclonal antibody-mediated tumor cell killing mechanisms: rational design of dosing strategies. Mol Pharmacol 2014; 86:485-91. [PMID: 24944188 PMCID: PMC4201137 DOI: 10.1124/mol.114.092684] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 06/18/2014] [Indexed: 11/22/2022] Open
Abstract
Since approval of rituximab for treatment of B cell non-Hodgkin lymphoma, development of monoclonal antibodies (mAbs) for cancer treatment and elucidation of their cytotoxic mechanisms have been subject to intense investigations. Compelling evidence indicates that rituximab and another CD20 mAb, ofatumumab, must use the body's cellular and humoral immune effector functions to kill malignant cells. Other U.S. Food and Drug Administration-approved mAbs, including obinutuzumab, cetuximab, and trastuzumab, require, in part, these effector mechanisms to eliminate tumor cells. Although gram quantities of mAbs can be administered to patients, our investigations of CD20 mAb-based therapies for chronic lymphocytic leukemia (CLL), including correlative measurements in clinical trials and studies with primary cells and cell lines, indicate that effector mechanisms necessary for mAb activity can be saturated or exhausted if tumor burdens are high, thus substantially compromising the efficacy of high-dose mAb therapy. Under these conditions, another reaction (trogocytosis) predominates in which bound CD20 mAb and CD20 are removed from targeted cells by effector cells that express Fcγ receptors, thereby allowing malignant cells to escape unharmed and continue to promote disease pathology. To address this problem, we propose that a low-dose strategy, based on administering 30-50 mg of CD20 mAb three times per week, may be far more effective for CLL than standard dosing because it will minimize effector function saturation and reduce trogocytosis. This approach may have general applicability to other mAbs that use immune effector functions, and could be formulated into a subcutaneous treatment strategy that would be more accessible and possibly more efficacious for patients.
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Affiliation(s)
- Ronald P Taylor
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Margaret A Lindorfer
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia
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