Crosstalk between Medulloblastoma Cells and Endothelium Triggers a Strong Chemotactic Signal Recruiting T Lymphocytes to the Tumor Microenvironment Vita S. Salsman1,2,3, Kevin K. H. Chow1,2,3, Donald R. Shaffer1,2,3, Huseyin Kadikoy1,2,3, Xiao-Nan Li2,3, Claudia Gerken1,2,3, Laszlo Perlaky2,3, Leonid S. Metelitsa1,2,3,4, Xiuhua Gao1,2,3,4, Meena Bhattacharjee4, Karen Hirschi1,4, Helen E. Heslop1,2,3,5, Stephen Gottschalk1,2,3,4, Nabil Ahmed1,2,3* 1 Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, United States of America, 2 Texas Children’s Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America, 3 Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America, 4 Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America, 5 Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America Abstract Cancer cells can live and grow if they succeed in creating a favorable niche that often includes elements from the immune system. While T lymphocytes play an important role in the host response to tumor growth, the mechanism of their trafficking to the tumor remains poorly understood. We show here that T lymphocytes consistently infiltrate the primary brain cancer, medulloblastoma. We demonstrate, both in vitro and in vivo, that these T lymphocytes are attracted to tumor deposits only after the tumor cells have interacted with tumor vascular endothelium. Macrophage Migration Inhibitory Factor (MIF)’’ is the key chemokine molecule secreted by tumor cells which induces the tumor vascular endothelial cells to secrete the potent T lymphocyte attractant ‘‘Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES).’’ This in turn creates a chemotactic gradient for RANTES-receptor bearing T lymphocytes. Manipulation of this pathway could have important therapeutic implications. Citation: Salsman VS, Chow KKH, Shaffer DR, Kadikoy H, Li X-N, et al. (2011) Crosstalk between Medulloblastoma Cells and Endothelium Triggers a Strong Chemotactic Signal Recruiting T Lymphocytes to the Tumor Microenvironment. PLoS ONE 6(5): e20267. doi:10.1371/journal.pone.0020267 Editor: Lin Zhang, University of Pennsylvania, United States of America Received April 1, 2011; Accepted April 16, 2011; Published May 27, 2011 Copyright: 2011 Salsman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors were supported by P30CA125123, grants from the Clayton Foundation for Research, the Dana Foundation, and the American Brain Tumor Association. HEH is supported by a Dan L. Duncan Chair. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: nahmed@bcm.edu Introduction Growing evidence indicates that cancer cells can only live and grow if they succeed in creating a niche that favors their survival and progression. [1] This microenvironment often includes vascular endothelial cells, supporting stromal cells as well as elements from the immune system. [2–5] T lymphocytes constitute one of the most important effector mechanisms of antitumor immunity and often contribute to the tumor microenvironment and their role remains controversial. [6] T lymphocytic infiltrates have been correlated with antitumor immunity and favorable outcomes in a number of tumors. [6–10] Other reports demonstrated the facilitative role of infiltrating T lymphocytes to the survival and progression of tumor cells. [11–13] These observations point out to the potential duality of the role of T lymphocytes in the tumor microenvironment: possibly attempting to cordon the tumor progression but also sustaining the tumor niche. While there is substantial knowledge about the sequence of events creating the signals that drive leukocyte infiltration in models of inflammation and autoimmune disease, [14–24] little is known about the mechanistic events that attract T lymphocytes to the tumor microenvironment. Decoding such events would increase our understanding of the interaction between the tumor cells and tumor infiltrating T lymphocytes and help develop strategies to enhance or block this crosstalk. Growing evidence supports the essential and complex role of the vascular endothelium in tumor biology and cancer progression. [25–27] It is now evident that the interactions between vascular endothelial cells and the tumor microenvironment may regulate tumor progression in a tumor-type-specific manner. [25] We show here, using medulloblastoma as a model, that T lymphocytes may only be attracted to tumor deposits if the tumor cells have interacted with the tumor vascular endothelium. Macrophage Migration Inhibitory Factor (MIF)’’ is the key primary chemokine molecule secreted by tumor cells which induces the potent T lymphocyte attractant ‘‘Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES)’’ from endothelial cells, which in turn creates a chemotactic gradient for RANTES-receptor bearing T lymphocytes. Manip- ulation of this pathway could have important therapeutic implications. PLoS ONE | www.plosone.org 1 May 2011 | Volume 6 | Issue 5 | e20267