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Cancer Immunology, Immunotherapy

, Volume 57, Issue 1, pp 123–131 | Cite as

Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy

  • Justin T. Jordan
  • Wei Sun
  • S. Farzana Hussain
  • Guillermo DeAngulo
  • Sujit S. Prabhu
  • Amy B. HeimbergerEmail author
Original Article

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.

Keywords

Gliomas Regulatory T cells Chemokines Tumor immunity 

Abbreviations

APC

Antigen presenting cell

BCNU

Carmustine [3-bis (2-chloroethyl)-1-nitrosourea]

ELISA

Enzyme-linked immunosorbent assay

FACS

Fluorescence-activated cell sorter

FITC

Fluorescein isothiocyanate

GBM

Glioblastoma multiforme

IL

Interleukin

MEM

Minimum essential medium

PBMC

Peripheral blood mononuclear cell

PBS

Phosphate-buffered saline

Treg

Regulatory T cell

Notes

Acknowledgments

We are grateful to Lamonne Crutcher for assistance in obtaining patient specimens. This work was supported by recruitment start-up funds for the Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center; by the National Brain Tumor Foundation Translational Grant; by The Rose Foundation; and by National Institutes of Health grant RO1 CA120813-01A1.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Justin T. Jordan
    • 1
  • Wei Sun
    • 1
  • S. Farzana Hussain
    • 1
  • Guillermo DeAngulo
    • 2
  • Sujit S. Prabhu
    • 1
  • Amy B. Heimberger
    • 1
    Email author
  1. 1.Department of Neurosurgery, Unit 442The University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Pediatrics, Unit 87The University of Texas M. D. Anderson Cancer CenterHoustonUSA

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