Macrophage-Mediated Trogocytosis Leads to Death of Antibody-Opsonized Tumor Cells

Understanding the complex behavior of effector cells such as monocytes or macrophages in regulating cancerous growth is of central importance for cancer immunotherapy. Earlier studies using CD20-specific antibodies have demonstrated that the Fcγ receptor (FcγR)–mediated transfer of the targeted receptors from tumor cells to these effector cells through trogocytosis can enable escape from antibody therapy, leading to the viewpoint that this process is protumorigenic. In the current study, we demonstrate that persistent trogocytic attack results in the killing of HER2-overexpressing breast cancer cells. Further, antibody engineering to increase FcγR interactions enhances this tumoricidal activity. These studies extend the complex repertoire of activities of macrophages to trogocytic-mediated cell death of HER2-overexpressing target cells and have implications for the development of effective antibody-based therapies. Mol Cancer Ther; 15(8); 1879–89. ©2016 AACR.

[1]  R. Jordan,et al.  Trastuzumab Triggers Phagocytic Killing of High HER2 Cancer Cells In Vitro and In Vivo by Interaction with Fcγ Receptors on Macrophages , 2015, The Journal of Immunology.

[2]  M. Lindorfer,et al.  Fcγ-receptor-mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments. , 2015, Blood.

[3]  Ronald P. Taylor,et al.  Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies , 2014, Molecular Pharmacology.

[4]  S. Ram,et al.  The level of HER2 expression is a predictor of antibody-HER2 trafficking behavior in cancer cells , 2014, mAbs.

[5]  A. Ardizzoni,et al.  Trastuzumab emtansine is active on HER-2 overexpressing NSCLC cell lines and overcomes gefitinib resistance , 2014, Molecular Cancer.

[6]  C. Klein,et al.  Glycoengineering of Therapeutic Antibodies Enhances Monocyte/Macrophage-Mediated Phagocytosis and Cytotoxicity , 2014, The Journal of Immunology.

[7]  P. Kubes,et al.  Macrophages eliminate circulating tumor cells after monoclonal antibody therapy. , 2014, The Journal of clinical investigation.

[8]  Sally E. Ward,et al.  Engineering multivalent antibodies to target heregulin-induced HER3 signaling in breast cancer cells , 2013, mAbs.

[9]  P. Bousso,et al.  The mechanism of anti-CD20-mediated B cell depletion revealed by intravital imaging. , 2013, The Journal of clinical investigation.

[10]  C. Klein,et al.  Preclinical Activity of the Type II CD20 Antibody GA101 (Obinutuzumab) Compared with Rituximab and Ofatumumab In Vitro and in Xenograft Models , 2013, Molecular Cancer Therapeutics.

[11]  D. Davis,et al.  Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity. , 2013, Blood.

[12]  H. Harigae,et al.  Fratricide of natural killer cells dressed with tumor-derived NKG2D ligand , 2013, Proceedings of the National Academy of Sciences.

[13]  Jens-Peter Volkmer,et al.  Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response , 2013, Proceedings of the National Academy of Sciences.

[14]  S. Jung,et al.  Effective phagocytosis of low Her2 tumor cell lines with engineered, aglycosylated IgG displaying high FcγRIIa affinity and selectivity. , 2013, ACS chemical biology.

[15]  R. Jordan,et al.  Tumor-Associated Macrophages Promote Invasion while Retaining Fc-Dependent Anti-Tumor Function , 2012, The Journal of Immunology.

[16]  S. Ram,et al.  3D single molecule tracking with multifocal plane microscopy reveals rapid intercellular transferrin transport at epithelial cell barriers. , 2012, Biophysical journal.

[17]  J. Ravetch,et al.  Mouse model recapitulating human Fcγ receptor structural and functional diversity , 2012, Proceedings of the National Academy of Sciences.

[18]  J. Jansen,et al.  Both activating and inhibitory Fc gamma receptors mediate rituximab-induced trogocytosis of CD20 in mice. , 2012, Immunology letters.

[19]  G. Pietersz,et al.  Fc receptor-targeted therapies for the treatment of inflammation, cancer and beyond , 2012, Nature Reviews Drug Discovery.

[20]  P. Parren,et al.  Loss of CD20 and Bound CD20 Antibody from Opsonized B Cells Occurs More Rapidly Because of Trogocytosis Mediated by Fc Receptor-Expressing Effector Cells Than Direct Internalization by the B Cells , 2011, The Journal of Immunology.

[21]  P. Mero,et al.  Dynamics of Macrophage Trogocytosis of Rituximab-Coated B Cells , 2011, PloS one.

[22]  Ash A. Alizadeh,et al.  Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma , 2010, Cell.

[23]  H. Komatsu [Antibody therapy in cancer]. , 2010, Nihon rinsho. Japanese journal of clinical medicine.

[24]  Jeffrey W. Pollard,et al.  Macrophage Diversity Enhances Tumor Progression and Metastasis , 2010, Cell.

[25]  E. Joly,et al.  The Direction of Plasma Membrane Exchange between Lymphocytes and Accessory Cells by Trogocytosis Is Influenced by the Nature of the Accessory Cell , 2010, The Journal of Immunology.

[26]  D. Davis Mechanisms and functions for the duration of intercellular contacts made by lymphocytes , 2009, Nature Reviews Immunology.

[27]  A. Sica,et al.  M2 Macrophages Phagocytose Rituximab-Opsonized Leukemic Targets More Efficiently than M1 Cells In Vitro1 , 2009, The Journal of Immunology.

[28]  M. Lindorfer,et al.  Within Peripheral Blood Mononuclear Cells, Antibody-Dependent Cellular Cytotoxicity of Rituximab-Opsonized Daudi cells Is Promoted by NK Cells and Inhibited by Monocytes due to Shaving1 , 2008, The Journal of Immunology.

[29]  J. Desjarlais,et al.  Optimization of antibody binding to FcγRIIa enhances macrophage phagocytosis of tumor cells , 2008, Molecular Cancer Therapeutics.

[30]  J. Xiang,et al.  Intercellular Trogocytosis Plays an Important Role in Modulation of Immune Responses , 2008, Cellular and Molecular Immunology.

[31]  G. A. Lazar,et al.  Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective. , 2007, Drug discovery today.

[32]  J. Stavenhagen,et al.  Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcgamma receptors. , 2007, Cancer research.

[33]  Zhuo Gan,et al.  Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy , 2007, Proceedings of the National Academy of Sciences.

[34]  Michael E. Williams,et al.  Thrice-Weekly Low-Dose Rituximab Decreases CD20 Loss via Shaving and Promotes Enhanced Targeting in Chronic Lymphocytic Leukemia1 , 2006, The Journal of Immunology.

[35]  S. Krause,et al.  Ex Vivo-activated Human Macrophages Kill Chronic Lymphocytic Leukemia Cells in the Presence of Rituximab: Mechanism of Antibody-dependent Cellular Cytotoxicity and Impact of Human Serum , 2006, Journal of immunotherapy.

[36]  J. Ravetch,et al.  Divergent Immunoglobulin G Subclass Activity Through Selective Fc Receptor Binding , 2005, Science.

[37]  S. Ram,et al.  Simultaneous imaging of different focal planes in fluorescence microscopy for the study of cellular dynamics in three dimensions , 2004, IEEE Transactions on NanoBioscience.

[38]  M. Sliwkowski,et al.  Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. , 2004, Cancer cell.

[39]  Raimund J. Ober,et al.  Visualizing the Site and Dynamics of IgG Salvage by the MHC Class I-Related Receptor, FcRn1 , 2004, The Journal of Immunology.

[40]  E. Joly,et al.  What is trogocytosis and what is its purpose? , 2003, Nature Immunology.

[41]  Hyun-soo Cho,et al.  Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab , 2003, Nature.

[42]  Brian Higgins,et al.  Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. , 2002, Cancer cell.

[43]  R. Michel,et al.  Intracellular accumulation of the anti-CD20 antibody 1F5 in B-lymphoma cells. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[44]  M. Jackson,et al.  TCR-Mediated internalization of peptide-MHC complexes acquired by T cells. , 1999, Science.

[45]  S. Ho,et al.  Engineering hybrid genes without the use of restriction enzymes: gene splicing by overlap extension. , 1989, Gene.

[46]  S. Silverstein,et al.  Studies on the mechanism of phagocytosis. II. The interaction of macrophages with anti-immunoglobulin IgG-coated bone marrow-derived lymphocytes , 1976, The Journal of experimental medicine.

[47]  M. Raff,et al.  Redistribution and pinocytosis of lymphocyte surface immunoglobulin molecules induced by anti-immunoglobulin antibody. , 1971, Nature: New biology.

[48]  Ira Mellman,et al.  Cell biology of antigen processing in vitro and in vivo. , 2005, Annual review of immunology.

[49]  C. Harding,et al.  Pathways of antigen processing. , 1991, Current opinion in immunology.

[50]  D. Scheinberg,et al.  Monoclonal antibody therapy of cancer. , 1990, Cancer chemotherapy and biological response modifiers.