Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy.
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.
Jordan
Justin T
JT
Department of Neurosurgery, Unit 442, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
Sun
Wei
W
Hussain
S Farzana
SF
DeAngulo
Guillermo
G
Prabhu
Sujit S
SS
Heimberger
Amy B
AB
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000276:immunology*; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000187:drug effects / Q000378:metabolism; D054422:Chemokine CCL22 / Q000187:drug effects / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis* / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003593:Cytoplasm / Q000737:chemistry; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D054390:Receptors, CCR2 / Q000096:biosynthesis; D054398:Receptors, CCR4 / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D000077204:Temozolomide
D000970:Antineoplastic Agents; C515334:CCR2 protein, human; C515354:CCR4 protein, human; D018932:Chemokine CCL2; D054422:Chemokine CCL22; D018925:Chemokines; D054390:Receptors, CCR2; D054398:Receptors, CCR4; D003606:Dacarbazine; D002330:Carmustine; D000077204:Temozolomide