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

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

An Erratum to this article was published on 20 September 2007

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.

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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

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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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Authors and Affiliations

  1. Department of Neurosurgery, Unit 442, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Justin T. Jordan, Wei Sun, S. Farzana Hussain, Sujit S. Prabhu & Amy B. Heimberger

  2. Department of Pediatrics, Unit 87, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Guillermo DeAngulo

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  1. Justin T. Jordan
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  2. Wei Sun
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  3. S. Farzana Hussain
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  4. Guillermo DeAngulo
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  5. Sujit S. Prabhu
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  6. Amy B. Heimberger
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Corresponding author

Correspondence to Amy B. Heimberger.

Additional information

Justin T. Jordan and Wei Sun are contributed equally to this work.

An erratum to this article can be found at http://dx.doi.org/10.1007/s00262-007-0403-3

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Jordan, J.T., Sun, W., Hussain, S.F. et al. Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunol Immunother 57, 123–131 (2008). https://doi.org/10.1007/s00262-007-0336-x

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