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Originally published online as doi:10.2353/ajpath.2009.081034 on July 23, 2009

Published online before print July 23, 2009
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(American Journal of Pathology. 2009;175:786-798.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081034

Infiltrating CTLs in Human Glioblastoma Establish Immunological Synapses with Tumorigenic Cells

Carlos Barcia, Jr*{dagger}, Aurora Gómez*{dagger}, José M. Gallego-Sanchez{ddagger}, Ana Perez-Vallés§, Maria G. Castro, Pedro R. Lowenstein, Carlos Barcia, Sr{ddagger} and Maria-Trinidad Herrero*{dagger}

From the Clinical and Experimental Neuroscience,* Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas,{dagger} School of Medicine, University of Murcia, Campus de Espinardo, Murcia, Spain; the Departments of Neurosurgery,{ddagger} and Pathology,§ Hospital General Universitario de Valencia, Valencia, Spain; and the Board of Governors’ Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, and the Departments of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California

The immunological synapse between T cells and tumor cells is believed to be important for effective tumor clearance. However, the immunological synapse has never been imaged or analyzed in detail in human tissue. In this work, intercellular interactions between T cells and tumor cells were analyzed in detail in human glioblastoma. After characterization of the population of infiltrating T cells by multiple immunofluorescence staining and stereological quantification, the microanatomy of T cell-tumor cell intercellular communication was analyzed in detail using confocal microscopy and three-dimensional rendering. Cytotoxic T lymphocytes that infiltrated human glioblastoma underwent rearrangement when in contact with tumor cells, to form a three-dimensional structure in the intercellular contact area; this was characterized by microclusters of the CD3/TCR complex, re-arrangement of the cytoskeleton, and granzyme B polarization. In addition, such T cell-targeted cells show fragmentation of the microtubular system and increased expression levels of cleaved caspase 3, which suggests that cytotoxic T lymphocytes likely provoke changes in tumor cells and subsequently induce cell death. These results show that the formation of the cytotoxic T lymphocyte immunological synapse occurs in human tissue and may be relevant for the effective immune-mediated clearance of tumorigenic cells, therefore opening up new avenues for glioblastoma immunotherapy.






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Copyright © 2009 by the American Society for Investigative Pathology.