Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. 2008

Justin T Jordan, and Wei Sun, and S Farzana Hussain, and Guillermo DeAngulo, and Sujit S Prabhu, and Amy B Heimberger
Department of Neurosurgery, Unit 442, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

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.

UI MeSH Term Description Entries
D001932 Brain Neoplasms Neoplasms of the intracranial components of the central nervous system, including the cerebral hemispheres, basal ganglia, hypothalamus, thalamus, brain stem, and cerebellum. Brain neoplasms are subdivided into primary (originating from brain tissue) and secondary (i.e., metastatic) forms. Primary neoplasms are subdivided into benign and malignant forms. In general, brain tumors may also be classified by age of onset, histologic type, or presenting location in the brain. Brain Cancer,Brain Metastases,Brain Tumors,Cancer of Brain,Malignant Primary Brain Tumors,Neoplasms, Intracranial,Benign Neoplasms, Brain,Brain Neoplasm, Primary,Brain Neoplasms, Benign,Brain Neoplasms, Malignant,Brain Neoplasms, Malignant, Primary,Brain Neoplasms, Primary Malignant,Brain Tumor, Primary,Brain Tumor, Recurrent,Cancer of the Brain,Intracranial Neoplasms,Malignant Neoplasms, Brain,Malignant Primary Brain Neoplasms,Neoplasms, Brain,Neoplasms, Brain, Benign,Neoplasms, Brain, Malignant,Neoplasms, Brain, Primary,Primary Brain Neoplasms,Primary Malignant Brain Neoplasms,Primary Malignant Brain Tumors,Benign Brain Neoplasm,Benign Brain Neoplasms,Benign Neoplasm, Brain,Brain Benign Neoplasm,Brain Benign Neoplasms,Brain Cancers,Brain Malignant Neoplasm,Brain Malignant Neoplasms,Brain Metastase,Brain Neoplasm,Brain Neoplasm, Benign,Brain Neoplasm, Malignant,Brain Neoplasms, Primary,Brain Tumor,Brain Tumors, Recurrent,Cancer, Brain,Intracranial Neoplasm,Malignant Brain Neoplasm,Malignant Brain Neoplasms,Malignant Neoplasm, Brain,Neoplasm, Brain,Neoplasm, Intracranial,Primary Brain Neoplasm,Primary Brain Tumor,Primary Brain Tumors,Recurrent Brain Tumor,Recurrent Brain Tumors,Tumor, Brain
D002330 Carmustine A cell-cycle phase nonspecific alkylating antineoplastic agent. It is used in the treatment of brain tumors and various other malignant neoplasms. (From Martindale, The Extra Pharmacopoeia, 30th ed, p462) This substance may reasonably be anticipated to be a carcinogen according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (From Merck Index, 11th ed) BCNU,1,3-Bis(2-Chloroethyl)-1-Nitrosourea,BiCNU,FIVB,N,N'-Bis(2-Chloroethyl)-N-Nitrosourea,Nitrumon
D002634 Chemotaxis, Leukocyte The movement of leukocytes in response to a chemical concentration gradient or to products formed in an immunologic reaction. Leukotaxis,Leukocyte Chemotaxis
D003593 Cytoplasm The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990) Protoplasm,Cytoplasms,Protoplasms
D003606 Dacarbazine An antineoplastic agent. It has significant activity against melanomas. (from Martindale, The Extra Pharmacopoeia, 31st ed, p564) DTIC,5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide,Biocarbazine,DIC,DTIC-Dome,Decarbazine,Deticene,Dimethyl Imidazole Carboxamide,Dimethyl Triazeno Imidazole Carboxamide,ICDT,NSC-45388,Carboxamide, Dimethyl Imidazole,DTIC Dome,DTICDome,Imidazole Carboxamide, Dimethyl,NSC 45388,NSC45388
D004797 Enzyme-Linked Immunosorbent Assay An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. ELISA,Assay, Enzyme-Linked Immunosorbent,Assays, Enzyme-Linked Immunosorbent,Enzyme Linked Immunosorbent Assay,Enzyme-Linked Immunosorbent Assays,Immunosorbent Assay, Enzyme-Linked,Immunosorbent Assays, Enzyme-Linked
D005434 Flow Cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. Cytofluorometry, Flow,Cytometry, Flow,Flow Microfluorimetry,Fluorescence-Activated Cell Sorting,Microfluorometry, Flow,Cell Sorting, Fluorescence-Activated,Cell Sortings, Fluorescence-Activated,Cytofluorometries, Flow,Cytometries, Flow,Flow Cytofluorometries,Flow Cytofluorometry,Flow Cytometries,Flow Microfluorometries,Flow Microfluorometry,Fluorescence Activated Cell Sorting,Fluorescence-Activated Cell Sortings,Microfluorimetry, Flow,Microfluorometries, Flow,Sorting, Fluorescence-Activated Cell,Sortings, Fluorescence-Activated Cell
D005910 Glioma Benign and malignant central nervous system neoplasms derived from glial cells (i.e., astrocytes, oligodendrocytes, and ependymocytes). Astrocytes may give rise to astrocytomas (ASTROCYTOMA) or glioblastoma multiforme (see GLIOBLASTOMA). Oligodendrocytes give rise to oligodendrogliomas (OLIGODENDROGLIOMA) and ependymocytes may undergo transformation to become EPENDYMOMA; CHOROID PLEXUS NEOPLASMS; or colloid cysts of the third ventricle. (From Escourolle et al., Manual of Basic Neuropathology, 2nd ed, p21) Glial Cell Tumors,Malignant Glioma,Mixed Glioma,Glial Cell Tumor,Glioma, Malignant,Glioma, Mixed,Gliomas,Gliomas, Malignant,Gliomas, Mixed,Malignant Gliomas,Mixed Gliomas,Tumor, Glial Cell,Tumors, Glial Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077204 Temozolomide A dacarbazine derivative that is used as an alkylating antineoplastic agent for the treatment of MALIGNANT GLIOMA and MALIGNANT MELANOMA. 8-Carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one,CCRG 81045,CCRG-81045,M&B 39831,M&B-39831,Methazolastone,NSC 362856,NSC-362856,TMZ-Bioshuttle,TMZA-HE,Temodal,Temodar,Temozolomide Hexyl Ester,CCRG81045,M&B39831,NSC362856,TMZ Bioshuttle

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