Migration of cytotoxic T lymphocytes toward melanoma cells in three-dimensional organotypic culture is dependent on CCL2 and CCR4.
Studies in experimental animal models have demonstrated that chemokines produced by tumor cells attract chemokine receptor-positive T lymphocytes into the tumor area. However, in cancer patients, the role of chemokines in T lymphocyte trafficking toward human tumor cells is relatively unexplored. In the present study, the migration of a melanoma patient's CTL toward autologous tumor cells has been studied in a novel three-dimensional organotypic melanoma culture. In this model, CTL migrated toward tumor cells, resulting in tumor cell apoptosis. CTL migration was mediated by the CC chemokine receptor (CCR)4 expressed by the CTL and the CC chemokine ligand (CCL)2 secreted by the tumor cells, as evidenced by blockage of CTL migration by CCL2 or antibodies to CCL2 or CCR4. These results were confirmed in a Transwell migration assay in which the CTL actively migrated toward isolated CCL2 and migration was inhibited by anti-CCR4 antibody. These studies, together with previous studies in mice indicating regression of CCL2-transduced tumor cells, suggest that CCL2 may be useful as an immunotherapeutic agent for cancer patients.
Zhang
Tianqian
T
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104-4268, USA.
Somasundaram
Rajasekharan
R
Berencsi
Klara
K
Caputo
Laura
L
Gimotty
Phyllis
P
Rani
Pyapalli
P
Guerry
DuPont
D
Swoboda
Rolf
R
Herlyn
Dorothee
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D018929:Cell Culture Techniques; D018932:Chemokine CCL2 / Q000276:immunology* / Q000627:therapeutic use; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051379:Mice; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; C111835:CCL2 protein, human; C515354:CCR4 protein, human; C515355:Ccr4 protein, mouse; D018932:Chemokine CCL2; D054398:Receptors, CCR4; D019707:Receptors, Chemokine