IMMUNOLOGY RESEARCH
Authors: K. Dziurzynski, J. Wei, W. Qiao, M. A. Hatiboglu, L.-Y. Kong, A. Wu, Y. Wang, D. P. Cahill, N. B. Levine, S. S. Prabhu, G. Rao, R. Sawaya, A. B. Heimberger, J. de Vrij, K. M. C. Kwappenberg, S. L. N. Maas, A. Kleijn, M. L. Lamfers, C. M. F. Dirven, M. W. Schilham, M. L. D. Broekman, A. Garcia-Velasco, S. del Barco, R. Alvarez, R. Fuentes, J. Marruecos, O. Hernando, C. Rubio, J. Menendez, J. Brunet, M. Hidalgo, T.-Y. Jung, Y.-H. Kim, S. Jung, W.-Y. Jang, K.-S. Moon, I.-Y. Kim, M.-C. Lee, J.-J. Lee, G. Kohanbash, K. McKaveney, M. Sakaki, A. Mintz, J. Ohlfest, M. Bondy, M. Fujita, H. Okada, Y. Liu, M. Ohno, H. Okada, B. Raychaudhuri, M. A. Vogelbaum, K. Z. Sabin, D. Lebert, V. Thibado, R. Rovin, J. Lawrence, R. Winn, A. Kleijn, J. Kloezeman, E. Treffers-Westerlaken, G. Fulci, S. Leenstra, C. Dirven, R. Debets, M. Lamfers, Z. Belcaid, J. A. Phallen, J. Zeng, A. P. See, E. Albesiano, N. M. Durham, B. Tyler, H. Brem, D. M. Pardoll, C. Drake, M. Lim, T. R. Sippel, J. White, R. Russel, A. Waziri, G. Kohanbash, E. Ishikawa, M. Fujita, M. Ohno, Y. Liu, M. Sakaki, M. Ikeura, M. Scheurer, M. Bondy, H. Okada, H. Q. Yi, Y. L. Duan, C. Q. Yang, K. S. Seo, G. Bohach, E. Fortunato, M. H. Luo
Journal: Neuro-Oncology (2011)

We have identified a mechanism by which cytomegalovirus (CMV) interleukin-10 (IL-10) is utilized by glioblastoma multiforme (GBM) to maintain the immunosuppressive microenvironment.CMV has been ubiquitously detected within high-grade gliomas, but its role has not been fully elicited.GBMs harvested ex vivo were analyzed by flow cytometry to determine CMV antigen expression.Distinct expressing subsets of cells, such as the myeloid lineage and CD133+ cells, were identified.CMV antigens US28, pp65, IE1, and gB were also present within four individual and fully characterized human GBM-derived glioma cancer stem cell (gCSC) populations as ascertained by flow cytometry.These gCSCs produce CMV IL-10 in a range from 5.62 to 111.11 pg/mL/10 6 cells/day.When human CD14+ monocytes, precursor cells to macrophages/microglia, were exposed to gCSC-conditioned medium or recombinant CMV IL-10, there was a marked increase in the expression of immune-suppressive factors such as B7-H1, p-STAT3, VEGF, and TGF-beta.Concurrently, anti-tumor and pro-immune MHC II and CD86 were down-regulated and the expression pattern of immune markers was similar to the phenotype of glioma-associated macrophages/microglia.Exposure of CD14+ cells to CMV IL-10 induced the up-regulation of IE1, a marker of transcriptional activity of CMV.Chemotaxis assays revealed that the supernatant from CD14+ cells exposed to CMV IL-10 was able to induce the migration of gCSCs compared with the supernatant from CD14+ cells cultured in medium alone.This result indicates that CMV subverts GBM-associated macrophages/microglia to support the immune-suppressive microenvironment by shifting their phenotype to the immune-suppressive M2.The shift is subsequent to activation of the STAT3 pathway, resulting in the propagation of glioma angiogenesis via an increase in VEGF and by increasing glioma invasion.Therapeutic strategies involving immune-mediated cytotoxic responses now include strategies to reverse tumor-mediated immune suppression.This study suggests that including CMV as a target could enhance the effectiveness of immunotherapy.