Preferential Migration of T Regulatory Cells Mediated by Glioma-Secreted Chemokines (49.3)

Abstract

Abstract Despite the immunogenicity of glioblastoma multiforme (GBM), the most common primary brain neoplasm, immune clearance of these tumors is still insufficient for tumor eradication and control. Elevated frequency of CD4+ CD25+FoxP3+ T regulatory (Treg) cells in peripheral blood or tumor-infiltrating lymphocytes has been observed in patients with various solid tumors including glioblastoma. This presence of high Treg fraction contributes to the dismal immune responses generated within these patients and prompted us to investigate the possible mechanism of Tregs selective recruitment in GBM patients. We hypothesized that the chemokines produced by gliomas induce this preferentially Treg migration. In the human malignant glioma cell lines D-54, U-87, U-251 and LN229, the chemokines CCL22 and CCL2 were preferentially produced compared to CXCL9, CCL3, and CCL4 by using cytokine flow cytometry and confirmed with ELISA. Additionally, gliomas obtained directly from human patients demonstrated a similar chemokine expression profile. Glioma supernatants, recombinant CCL2 and CCL22 could induce the migration of Tregs, which could be blocked by neutralizing antibodies to these chemokines. Flow cytometric investigation of the expressions of the CCL2 and CCL22 chemokine receptors CCR2 and CCR4 on peripheral T cells indicated that GBM patients have more CD4+CD25+ T cells that express CCR2 (26%) and CCR4 (53%) in contrast to the CD4+CD25+ T subset from normal individuals that express CCR2 (17%) and CCR4 (42%). These data indicate that gliomas modulate immunosuppression by the selective recruitment of Tregs into the tumor microenvironment and those therapies that modulate this interaction may be potentially synergistic with tumor immunotherapies.