title: Application of paclitaxel in low non-cytotoxic doses supports vaccination with melanoma antigens in normal mice.
abstract: Chemotherapeutic agents such as paclitaxel applied in ultra-low, non-cytotoxic doses were previously shown to stimulate dendritic cell activity and anti-tumor immune responses upon vaccination in mouse transplantable tumor models. However, the mechanisms of these alterations-termed chemoimmunomodulation or chemomodulation-are still not clear. This study investigated the effect of paclitaxel applied in ultra-low, non-cytotoxic doses on the efficiency of immunization of healthy C57BL/6 mice with the peptide derived from tyrosinase related protein (TRP)-2 as a model melanoma antigen. Using an IFNγ ELISPOT assay, it was found that administration of 1 mg paclitaxel/kg in combination with the peptide vaccination strongly increased the frequencies of TRP-2 specific spleen T-cells as compared to levels due to the vaccination alone. This was associated with a significant decrease in the levels of regulatory T-cells (T(reg)) and immature myeloid cells (known as a counterpart of myeloid derived suppressor cells [MDSC] in healthy mice). Such impairments of potential immunosuppressive cells were found to correlate with a strong increase in the amount of effector CD8+ and CD4+ T-cells in the bone marrow and spleen. Furthermore, in paclitaxel-treated mice, a significant augmentation of natural killer (NK) cell numbers in the bone marrow and their ability to produce IFNγ were observed. In addition, the level of NK-T-cells in the lymph nodes was also increased. It is suggested that paclitaxel applied in ultra-low, non-cytotoxic doses may potentially enhance the efficacy of anti-tumor vaccinations by neutralizing immunosuppressive T(reg) and MDSC populations in tumor-bearing hosts.
authors.affiliation: Skin Cancer Unit, German Cancer Research Center and University Hospital Mannheim, Heidelberg, Germany. a.sevko@dkfz.de
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sevko
authors.forename: Veronika
authors.initials: V
authors.lastname: Kremer
authors.forename: Christine
authors.initials: C
authors.lastname: Falk
authors.forename: Ludmila
authors.initials: L
authors.lastname: Umansky
authors.forename: Michael R
authors.initials: MR
authors.lastname: Shurin
authors.forename: Galina V
authors.initials: GV
authors.lastname: Shurin
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D007111:Immunity, Cellular / Q000187:drug effects; D019746:Intramolecular Oxidoreductases / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D058950:Melanoma-Specific Antigens / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014611:Vaccination
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019496:Cancer Vaccines; D058950:Melanoma-Specific Antigens; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase; D017239:Paclitaxel