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An ultrastructural investigation of tumors undergoing regression mediated by immunotherapy

2017; Impact Journals LLC; Volume: 8; Issue: 70 Linguagem: Inglês

10.18632/oncotarget.23215

1949-2553

Jennifer A. Westwood, Sarah Ellis, Jill Danne, Chad Johnson, Viola Oorschot, Georg Ramm, David C. Tscharke, Alexander J. Davenport, James C. Whisstock, Phillip K. Darcy, Michael H. Kershaw, Clare Y. Slaney,

Cancer Immunotherapy and Biomarkers

// Jennifer A. Westwood 1 , Sarah Ellis 1, 2 , Jill Danne 2 , Chad Johnson 2 , Viola Oorschot 3 , Georg Ramm 3 , David C. Tscharke 4 , Alexander J. Davenport 1 , James C. Whisstock 5 , Phillip K. Darcy 1, 2 , Michael H. Kershaw 1, 2, * and Clare Y. Slaney 1, 2, * 1 Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Australia 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia 3 Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Clayton, Australia 4 John Curtin School of Medical Research, Australian National University, Canberra, Australia 5 The ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, Australia * These authors have contributed equally to this work Correspondence to: Clare Y. Slaney, email: clare.slaney@petermac.org Keywords: electron microscopy; tumor regression; cancer vaccine; breast cancer; apoptosis Received: May 24, 2017     Accepted: July 14, 2017     Published: December 14, 2017 ABSTRACT While immunotherapy employing chimeric antigen receptor (CAR) T cells can be effective against a variety of tumor types, little is known about what happens within the tumor at an ultrastructural level during tumor regression. Here, we used transmission electron microscopy to investigate morphologic and cellular features of tumors responding to immunotherapy composed of adoptive transfer of dual-specific CAR T cells and a vaccine, supported by preconditioning irradiation and interleukin-2. Tumors responded rapidly, and large areas of cell death were apparent by 4 days after treatment. The pleomorphic and metabolically active nature of tumor cells and phagocytic activity of macrophages were apparent in electron microscopic images of tumors prior to treatment. Following treatment, morphologic features of various types of tumor cell death were observed, including apoptosis, paraptosis and necrosis. Large numbers of lipid droplets were evident in tumor cells undergoing apoptosis. Macrophages were the predominant leukocyte type infiltrating tumors before treatment. Macrophages decreased in frequency and number after treatment, whereas an increasing accumulation of neutrophils and T lymphocytes was observed following treatment. Phagocytic activity of macrophages and neutrophils was apparent, while T cells could be observed in close association with tumor cells with potential immunological synapses present. These observations highlight the cellular composition and ultrastructural appearance of tumors undergoing regression mediated by immunotherapy.