title: Multidrug resistance-1 (MDR-1): a new target for T cell-based immunotherapy.
abstract: Acquired multidrug resistance (MDR) remains a major challenge in the treatment of cancer with chemotherapeutic drugs. It can be mediated by the up-regulated expression of different proteins within the tumor cell membrane. Here, we used murine multidrug resistance-1 (MDR-1) as a target-antigen for the immunotherapy of cancer. We successfully demonstrated that peripheral T cell tolerance can be broken by oral administration of a DNA vaccine encoding MDR-1 and carried by attenuated Salmonella typhimurium to secondary lymphoid organs. Thus, mice, immunized orally three times at 2-wk intervals and challenged 2 wk thereafter with either MDR-1 expressing CT-26 colon carcinoma cells or MDR-1 expressing Lewis lung carcinoma cells, revealed a significant increase in life span. This was evident, when compared with animals either vaccinated with the empty control vector or challenged with the parental cell lines lacking overexpression of MDR-1. The immune response induced was antigen-specific and CD8+ T cell-mediated. The presence of the target antigen led to up-regulation of activation markers on CD8+ T cells and resulted in a strong cytotoxic T cell response as well as lysis of tumor target cells in vitro. We furthermore established the vaccine to be an effective treatment for established multi-drug-resistant tumor metastases, resulting in a significantly increased life span of experimental animals. Absence of CD8+ T cells due to in vivo depletion led to abrogation of effectiveness. Taken together, our results demonstrate that T cell tolerance against the MDR-1 self-antigen can be broken. It is anticipated that the combination of such an approach with chemotherapy could lead to more effective treatments of cancer.
authors.affiliation: Department of Radiation Oncology, Heidelberg Medical School, Heidelberg, Germany.
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Niethammer
authors.forename: Harald
authors.initials: H
authors.lastname: Wodrich
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
authors.forename: Kathrin
authors.initials: K
authors.lastname: Emmerich
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
authors.forename: Robert
authors.initials: R
authors.lastname: Krempien
authors.forename: Juergen
authors.initials: J
authors.lastname: Debus
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D019450:Genes, MDR / Q000235:genetics* / Q000276:immunology; D005822:Genetic Vectors / Q000096:biosynthesis / Q000235:genetics; D007109:Immunity / Q000502:physiology; D007114:Immunization / Q000379:methods; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D040521:Subcutaneous Tissue / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic / Q000379:methods; D014611:Vaccination / Q000379:methods
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019496:Cancer Vaccines