In vitro exposure to paclitaxel modulates integrin expression by human T lymphocytes and inhibits T cell adhesion to breast carcinoma cells.
Paclitaxel (Taxol) is a drug that is commonly used in the treatment of metastatic breast cancer. In this study, we investigated the effect of prior exposure to submaximal cytotoxic concentrations (EC(25) and EC(50)) of paclitaxel on the subsequent ability of human Jurkat T lymphocytes to adhere to monolayers of MDA-MB-435 human breast carcinoma cells. Jurkat T cells that survived culture for 24 h in the presence of paclitaxel (0.1 or 3 micro g/ml) exhibited a diminished ability to adhere to MDA-MB-435 breast cancer cell monolayers. Flow cytometric analysis of paclitaxel-treated Jurkat T cells revealed reduced surface expression of alphaL, alpha4, alpha5, and beta7 integrins, but normal beta1 integrin expression. These data suggest that paclitaxel interferes with the expression of alphaLbeta2 (LFA-1), alpha4beta1 (VLA-4), alpha5beta1 (VLA-5), and alpha4beta7 (LPAM-1) adhesion molecules by surviving T cells. Blocking experiments with antibodies against alphaL, alpha4, alpha5, beta1, and beta7 integrins revealed that adhesion of Jurkat T cells to MDA-MB-435 breast cancer cell monolayers was dependent upon alphaL, alpha4, and beta7 but not alpha5 or beta1 integrins. We conclude that prior exposure to paclitaxel caused a reduction in Jurkat T cell adhesion to MDA-MB-435 breast carcinoma cells by preventing optimal alphaLbeta2 and alpha4beta7 interactions with their corresponding ligands on tumor cells. A similar effect by paclitaxel on T lymphocytes of breast cancer patients may compromise cell-mediated anti-tumor immune responses.
Bhan
Vineet
V
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada.
Mader
Jamie S
JS
Hoskin
David W
DW
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism; D002277:Carcinoma / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D019169:Jurkat Cells; D017239:Paclitaxel / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D016023:Integrins; D017239:Paclitaxel