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Macrophage-Mediated Trogocytosis Leads to Death of Antibody-Opsonized Tumor Cells Ramraj Velmurugan1,2,3,5, Dilip K

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Macrophage-Mediated Trogocytosis Leads to Death of Antibody-Opsonized Tumor Cells Ramraj Velmurugan1,2,3,5, Dilip K Published OnlineFirst May 25, 2016; DOI: 10.1158/1535-7163.MCT-15-0335 Large Molecule Therapeutics Molecular Cancer Therapeutics Macrophage-Mediated Trogocytosis Leads to Death of Antibody-Opsonized Tumor Cells Ramraj Velmurugan1,2,3,5, Dilip K. Challa1,2,3,5, Sripad Ram5, Raimund J. Ober1,4,5,and E. Sally Ward1,2,5 Abstract Understanding the complex behavior of effector cells such as we demonstrate that persistent trogocytic attack results in the monocytes or macrophages in regulating cancerous growth is of killing of HER2-overexpressing breast cancer cells. Further, central importance for cancer immunotherapy. Earlier studies antibody engineering to increase FcgR interactions enhances using CD20-specific antibodies have demonstrated that the Fcg this tumoricidal activity. These studies extend the complex receptor (FcgR)–mediated transfer of the targeted receptors repertoire of activities of macrophages to trogocytic-mediated from tumor cells to these effector cells through trogocytosis cell death of HER2-overexpressing target cells and have impli- canenableescapefromantibody therapy, leading to the view- cations for the development of effective antibody-based ther- point that this process is protumorigenic. In the current study, apies. Mol Cancer Ther; 15(8); 1–11. Ó2016 AACR. Introduction of escape has been extensively studied for anti-CD20 antibodies (2, 3, 8, 9) and involves the depletion of target antigen from the Defining the consequences of the interactions of immune cell surface combined with the exhaustion of effector pathways. effector cells with cancer cells in the presence of tumor-specific These observations have led to the development of dosing regi- antibodies has direct relevance to both immunosurveillance and mens to reduce trogocytosis and minimize the protumorigenic cancer therapy. The effects of therapeutic antibodies can include effects during CD20 targeting (10). However, in different settings, the direct inhibition of cell signaling through growth factor it remains possible that trogocytosis results in tumor cell death. To receptor binding and the indirect consequences of tumor cell date, such analyses have been limited by the challenges in dis- opsonization and recruitment of effector cells such as macro- tinguishing trogocytosis from phagocytosis in effector:target cell phages or natural killer (NK) cells (1). For example, monocytes or cocultures. In the current study, we have developed an assay to macrophages can interact with antibody-opsonized tumor cells distinguish these two processes. This assay has been used to and engulf whole cells or internalize fragments of the target cell investigate whether trogocytosis leads to the attrition of HER2- plasma membrane during phagocytosis or trogocytosis, respec- overexpressing breast cancer cells. Establishment of trogocytosis tively (2–7). Although the tumoricidal effects of phagocytosis are as a pathway for tumor cell death has implications for strategies to clear, the effect of trogocytosis is less certain. It has been specu- optimize antibody-based therapies. lated that trogocytosis can have a positive effect during cancer The involvement of Fcg receptor (FcgR)–expressing effector therapy (6). Conversely, trogocytosis can result in escape from cells in antitumor effects has motivated the use of antibody antibody-dependent cell-mediated cytotoxicity, complement- engineering approaches directed toward the Fc region to enhance dependent cytotoxicity, or phagocytic cell death. This mechanism FcgR binding affinity (11–16). However, due to the challenges associated with quantitating trogocytosis, how Fc engineering 1Department of Molecular and Cellular Medicine, College of Medicine, affects this activity is unexplored. In addition, despite the expan- Texas A&M Health Science Center,College Station,Texas. 2Department sion in the development and use of antibody-based therapeutics of Microbial Pathogenesis and Immunology,Texas A&M Health Science 3 during the past decade (17, 18), the factors leading to the Center, Bryan, Texas. Biomedical Engineering Graduate Program, fi University of Texas Southwestern Medical Center, Dallas, Texas. induction of long-lived antitumor immunity are ill-de ned. Con- 4Department of Biomedical Engineering, Texas A&M University, Col- sequently, understanding the mechanisms through which macro- lege Station, Texas. 5Department of Immunology, UT Southwestern phages interact with tumor cells is not only important for Fc Medical Center, Dallas, Texas. engineering, but also has relevance to elucidating the subcellular Note: Supplementary data for this article are available at Molecular Cancer trafficking processes resulting in antigen acquisition and presen- Therapeutics Online (http://mct.aacrjournals.org/). tation by this antigen-presenting cell subset (19, 20). Current address for S. Ram: Pfizer, Inc., San Diego, CA. In the current study, we have used a novel approach to inves- Corresponding Authors: E. Sally Ward, Texas A&M Health Science Center, tigate the ability of macrophages of different sources to carry out College Station, TX 77843. Phone: 9798627612; Fax: 9794367612; E-mail: trogocytosis and phagocytosis of antibody-opsonized HER2-over- [email protected]; and Raimund J. Ober, Department of Bio- expressing breast cancer cells. The RAW264.7 macrophage cell line medical Engineering, Texas A&M University, College Station, TX 77843. E-mail: very rarely phagocytoses complete cells, but has trogocytic activity [email protected] similar to that of other macrophage types. Combined with analyses doi: 10.1158/1535-7163.MCT-15-0335 of apoptotic markers on opsonized target cells in the presence of Ó2016 American Association for Cancer Research. both human and mouse macrophages, this behavior has allowed www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst May 25, 2016; DOI: 10.1158/1535-7163.MCT-15-0335 Velmurugan et al. us to demonstrate that trogocytosis can lead to tumor cell death. comparison of WT trastuzumab and AE/ADE variants. Antibodies Using multifocal plane microscopy (MUM) to image dynamic specific for mouse FcgRs (clone X54-5/7.1 for FcgRI, 93 for FcgRII/ processes in three dimensions within cells (21, 22), we have also III, and 9E9 for FcgRIV) and the corresponding isotype controls analyzed the spatiotemporal aspects of trogocytosis in live cells. We were purchased from Biolegend. observe that this process involves the extension of opsonized tubules that are subsequently pinched off by the macrophage to Isolation of thioglycollate-elicited macrophages form internalized trogocytic compartments. Of direct relevance to C57BL/6J mice (purchased from The Jackson Laboratory) or Fc engineering, the enhancement of antibody affinity for FcgRs human FcgR-transgenic C57BL/6J mice (gift from Dr. Jeffrey results in increased trogocytosis and target cell death. Importantly, Ravetch, The Rockefeller University; ref. 26) were housed in a this higheractivity is only manifested in thepresence of physiologic pathogen-free animal facility at UT Southwestern Medical Center levels of intravenous gammaglobulin (IVIG). Collectively, these or the Texas A&M Health Science Center and handled according to studies indicate that trogocytosis can have tumoricidal effects that protocols approved by the Institutional Animal Care and Use are further enhanced by antibody engineering. Committees. Eight- to 12-week-old male mice were intraperito- neally injected with 3 mL aged thioglycollate (gift from Dr. Materials and Methods Chandrashekar Pasare, UT Southwestern Medical Center). After 72 hours, the mice were sacrificed and peritoneal macrophages Cell lines and primary cells isolated by peritoneal lavage. The macrophages were plated in the The murine macrophage cell lines RAW264.7 and J774A.1, and assay plates in complete DMEM containing 10% FCS, and assays the human breast cancer cell lines MDA-MB-453 and SK-BR-3 were were performed 1 to 3 days later using the same conditions as for purchased from the American Type Culture Collection (ATCC). The the macrophage cell lines. HCC1954 cell line was a gift from Drs. Adi Gazdar, John Minna, and Kenneth Huffman (UT Southwestern Medical Center, Dallas). Analyses of macrophage effects on tumor cell numbers The cell lines were maintained in the following media supplemen- Target cells were harvested, labeled with carboxyfluorescein ted with 10% FCS (Gemini Bio-products): macrophages, phenol succinimidyl ester (CFSE; Life Technologies), and mixed with red–free DMEM; MDA-MB-453, RPMI-1640; SK-BR-3, McCoy's. effector cells at the indicated effector:target ratios in wells of 48- HCC1954 cells were maintained in RPMI-1640 with 5% FCS. All well plates, centrifuged to obtain an even distribution in the wells experiments were conducted in medium containing FCS depleted and allowed to attach overnight. Cells were treated with 1 mg/mL of immunoglobulin G (IgG; 23), with the exception of experiments trastuzumab and incubated at 37C for 72 hours. The cells were using Fc-engineered antibodies. Identities of all cancer cell lines harvested by trypsinization, incubated with PerCP-labeled anti- were authenticated by short tandem repeat analysis on October 9, mouse CD45 antibody (clone 30-F11; BD Biosciences) and Alexa 2015 (University of Arizona Genetics Core). Murine macrophage 488–labeled pertuzumab, washed, and fixed with formalin. For cell lines purchased from the ATCC were maintained for less than 6 human macrophage
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