An ultrastructural investigation of tumors undergoing regression mediated by immunotherapy
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Jennifer A. Westwood1, Sarah Ellis1,2, Jill Danne2, Chad Johnson2, Viola Oorschot3, Georg Ramm3, David C. Tscharke4, Alexander J. Davenport1, James C. Whisstock5, Phillip K. Darcy1,2, Michael H. Kershaw1,2,* and Clare Y. Slaney1,2,*
1Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Australia
2Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
3Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Clayton, Australia
4John Curtin School of Medical Research, Australian National University, Canberra, Australia
5The ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, Australia
*These authors have contributed equally to this work
Clare Y. Slaney, email: [email protected]
Keywords: electron microscopy; tumor regression; cancer vaccine; breast cancer; apoptosis
Received: May 24, 2017 Accepted: July 14, 2017 Published: December 14, 2017
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.
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