title: Gemcitabine depletes regulatory T-cells in human and mice and enhances triggering of vaccine-specific cytotoxic T-cells.
abstract: Particle-mediated epidermal delivery (PMED) is a potent genetic vaccination method. However, a recent report found PMED only poorly and infrequently triggered antigen-specific cytotoxic T-cells in cancer patients. Here, we show that injection of the chemotherapeutic drug Gemcitabine in mice results in improvement of the efficacy of subsequent PMED vaccination against NY-ESO-1. We found in mice and in cancer patients that administration of Gemcitabine induces a transient reduction in the percentage of regulatory T-cells among CD4-positive cells. The higher relative sensitivity of regulatory T-cells compared to other CD4-positive T-cells toward cytostatic drugs can be linked to the higher frequency of proliferating cells in the regulatory compartment compared to the nonregulatory CD4-compartment in healthy people and cancer patients. Thus, by affecting regulatory T-cells more than other lymphocyte subsets, chemotherapeutic agents can create a transient hyperimmunoreactive window. Such a window would provide an ideal timepoint to administer a vaccine expected to induce a therapeutically relevant anticancer cytotoxic T-cell response.
authors.affiliation: Department of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich8044, Switzerland.
authors.forename: Lorna
authors.initials: L
authors.lastname: Rettig
authors.forename: Samuel
authors.initials: S
authors.lastname: Seidenberg
authors.forename: Iana
authors.initials: I
authors.lastname: Parvanova
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Samaras
authors.forename: Alessandra
authors.initials: A
authors.lastname: Curioni
authors.forename: Alexander
authors.initials: A
authors.lastname: Knuth
authors.forename: Steve
authors.initials: S
authors.lastname: Pascolo
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D000093542:Gemcitabine
chemical_list: D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D008565:Membrane Proteins; D003841:Deoxycytidine; D000093542:Gemcitabine