Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy
- 24 May 2007
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 57 (1), 123-131
- https://doi.org/10.1007/s00262-007-0336-x
Abstract
Despite the immunogenicity of glioblastoma multiforme (GBM), immune-mediated eradication of these tumors remains deficient. Regulatory T cells (Tregs) in the blood and within the tumor microenvironment of GBM patients are known to contribute to their dismal immune responses. Here, we determined which chemokine secreted by gliomas can preferentially induce Treg recruitment and migration. In the malignant human glioma cell lines D-54, U-87, U-251, and LN-229, the chemokines CCL22 and CCL2 were detected by intracellular cytokine analysis. Furthermore, tumor cells from eight patients with GBM had a similar chemokine expression profile. However, only CCL2 was detected by enzyme-linked immunosorbent assay, indicating that CCL2 may be the principal chemokine for Treg migration in GBM patients. Interestingly, the Tregs from GBM patients had significantly higher expression levels of the CCL2 receptor CCR4 than did Tregs from healthy controls. Glioma supernatants and the recombinant human chemokines CCL2 and CCL22 induced Treg migration and were blocked by antibodies to the chemokine receptors. Production of CCL2 by glioma cells could also be mitigated by the chemotherapeutic agents temozolomide and carmustine [3-bis (2-chloroethyl)-1-nitrosourea]. Our results indicate that gliomas augment immunosuppression by selective chemokine-mediated recruitment of Tregs into the tumor microenvironment and that modulating this interaction with chemotherapy could facilitate the development of novel immunotherapeutics to malignant gliomas.This publication has 32 references indexed in Scilit:
- The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses1Neuro-Oncology, 2006
- Migration of cytotoxic T lymphocytes toward melanoma cells in three‐dimensional organotypic culture is dependent on CCL2 and CCR4European Journal of Immunology, 2006
- Pharmacokinetic Considerations in the Treatment of CNS TumoursClinical Pharmacokinetics, 2006
- Anti-inflammatory Properties of the Novel Antitumor Agent Yondelis (Trabectedin): Inhibition of Macrophage Differentiation and Cytokine ProductionCancer Research, 2005
- Selective CD4+ Lymphopenia in Melanoma Patients Treated With Temozolomide: A Toxicity With Therapeutic ImplicationsJournal of Clinical Oncology, 2004
- Pharmacokinetics of the Carmustine ImplantClinical Pharmacokinetics, 2002
- Tumor antigens in astrocytic gliomasGlia, 1995
- Human astrocytomas and glioblastomas express monocyte chemoattractant protein‐1 (MCP‐1) in vivo and in vitroInternational Journal of Cancer, 1994
- Quantitative Study of Monocyte Chemoattractant Protein-1 (MCP-1) in Cerebrospinal Fluid and Cyst Fluid From Patients With Malignant GliomaJNCI Journal of the National Cancer Institute, 1993
- Divergent regulation of cell surface protease expression in HL-60 cells differentiated into macrophages with granulocyte macrophage colony stimulating factor or neutrophils with retinoic acidInternational Immunology, 1993