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Proteomic and immunologic analyses of brain tumor exosomes

Michael W. Graner^*,||,1,2, Oscar Alzate^,||, Angelika M. Dechkovskaia^,||, Jack D. Keene^,||, John H. Sampson^*,,||, Duane A. Mitchell^,|| and Darell D. Bigner^*,||

^* Department of Pathology,

Department of Neuroscience (Neuroproteomics),

Department of Surgery, and

Department of Molecular Genetics and Microbiology, Duke University Medical Center, and

^|| The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA

² Correspondence: Duke University Medical Center, Dept. of Pathology, Box 3050, 210 Sands Bldg., Durham, NC 27710, USA. E-mail: granermichael{at}yahoo.com

Brain tumors are horrific diseases with almost universally fatal outcomes; new therapeutics are desperately needed and will come from improved understandings of glioma biology. Exosomes are endosomally derived 30–100 nm membranous vesicles released from many cell types into the extracellular milieu; surprisingly, exosomes are virtually unstudied in neuro-oncology. These microvesicles were used as vaccines in other tumor settings, but their immunological significance is unevaluated in brain tumors. Our purpose here is to report the initial biochemical, proteomic, and immunological studies on murine brain tumor exosomes, following known procedures to isolate exosomes. Our findings show that these vesicles have biophysical characteristics and proteomic profiles similar to exosomes from other cell types but that brain tumor exosomes have unique features (e.g., very basic isoelectric points, expressing the mutated tumor antigen EGFRvIII and the putatively immunosuppressive cytokine TGF-β). Administration of such exosomes into syngeneic animals produced both humoral and cellular immune responses in immunized hosts capable of rejecting subsequent tumor challenges but failed to prolong survival in established orthotopic models. Control animals received saline or cell lysate vaccines and showed no antitumor responses. Exosomes and microvesicles isolated from sera of patients with brain tumors also possess EGFR, EGFRvIII, and TGF-β. We conclude that exosomes released from brain tumor cells are biochemically/biophysically like other exosomes and have immune-modulating properties. They can escape the blood-brain barrier, with potential systemic and distal signaling and immune consequences.—Graner, M. W., Alzate, O., Dechkovskaia, A. M., Keene, J. D., Sampson, J. H., Mitchell, D. A., Bigner, D. D. Proteomic and immunologic analyses of brain tumor exosomes.

Key Words: microvesicles • heat shock proteins • antibody • T cells • EGFRvIII • patient sera

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