Exposure to paclitaxel or vinblastine down-regulates CD11a and CD54 expression by P815 mastocytoma cells and renders the tumor cells resistant to killing by nonspecific cytotoxic T lymphocytes induced with anti-CD3 antibody.
Paclitaxel and vinblastine are drugs with anti-microtubule activity that are commonly used in the treatment of numerous types of cancer. In this study, we investigated the effect of prior exposure to submaximal cytotoxic concentrations (EC(25) and EC(50)) of paclitaxel or vinblastine on the subsequent susceptibility of surviving P815 murine mastocytoma cells to cytolysis by major histocompatibility complex (MHC)-unrestricted mouse cytotoxic T lymphocytes that had been induced with anti-CD3 antibody. P815 cells that had survived culture for 24 h in the presence of paclitaxel (5 or 50 micro g/ml) or vinblastine (1.5 or 15 micro g/ml) were rendered resistant to anti-CD3-activated killer-T (AK-T) cell-mediated cytolysis in a standard (51)Cr-release assay. Resistance to killing was associated with a reduced ability of AK-T cells to form conjugates with drug-treated P815 target cells, suggesting a possible effect on adhesion molecules. Flow cytometric analysis of paclitaxel- or vinblastine-treated P815 cells revealed reduced cell-surface expression of the adhesion molecules LFA-1 (CD11a /CD18) and ICAM-1 (CD54). Similar results were obtained following paclitaxel or vinblastine treatment of Yac-1 lymphoma cells. RT-PCR analysis revealed reduced levels of mRNAs coding for CD11a and CD54 in paclitaxel- or vinblastine-pretreated P815 cells. Collectively, these data lead us to conclude that paclitaxel and vinblastine render P815 mastocytoma cells resistant to T cell-mediated cytotoxicity by interfering with CD11a and CD54 expression by the tumor cells. A similar effect by these drugs on tumor cells and/or leukocytes in cancer patients might compromise tumor-specific cell-mediated immune responses.
Zhao
Chuanli
C
Department of Microbiology and Immunology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada.
Morgan
Max
M
Haeryfar
S M Mansour
SM
Blay
Jonathan
J
Hoskin
David W
DW
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D040881:CD11a Antigen / Q000096:biosynthesis*; D017252:CD3 Complex / Q000378:metabolism*; D002860:Chromium Radioisotopes / Q000627:therapeutic use; D015536:Down-Regulation; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology; D034801:Mastocytoma / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D017239:Paclitaxel / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D040881:CD11a Antigen; D017252:CD3 Complex; D002860:Chromium Radioisotopes; D018799:Intercellular Adhesion Molecule-1; D014747:Vinblastine; D017239:Paclitaxel