title: Humanized tumor mice--a new model to study and manipulate the immune response in advanced cancer therapy.
abstract: The immunological impact on antibody-based anticancer therapies remains incompletely understood due to the lack of appropriate animal models for in vivo analysis. Here, we present a novel humanized tumor mouse (HTM) model, generated by concurrent transplantation of human hematopoietic stem cells (HSCs) and human breast cancer cells in neonatal NOD-scid IL2Rγ(null)  mice. Five weeks after intrahepatic transplantation, a functional human immune system was developed in all organs, and, in addition, tumor cells were detectable in lung and bone marrow (early dissemination). After 3 months posttransplant, tumor-cell effusions and macroscopic tumors associated with liver or spleen were found. Furthermore, disseminated cells in different lymphoid and nonlymphoid organs were measurable. Tumor growth was accompanied by specific T-cell maturation and tumor cell-specific T-cell activation. In addition, Natural-Killer cell accumulation and activation were observed in HTM, which was further enhanced upon IL-15 treatment facilitating the possibility of immune cell modulation in, e.g., antibody-dependent cellular cytotoxicity-based immunotherapeutic approaches. This novel mouse model makes it possible to combine transfer of MHC mismatched tumor cells together with human HSCs resulting in a solid coexistence and interaction without evidence for rejection. Overall, humanized tumor mice represent a powerful in vivo model that for the first time permits the investigation of human immune system-related target cancer therapy and resistance.
authors.affiliation: Institute of Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Wege
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Ernst
authors.forename: Judith
authors.initials: J
authors.lastname: Eckl
authors.forename: Bernhard
authors.initials: B
authors.lastname: Frankenberger
authors.forename: Arabel
authors.initials: A
authors.lastname: Vollmann-Zwerenz
authors.forename: Daniela N
authors.initials: DN
authors.lastname: Männel
authors.forename: Olaf
authors.initials: O
authors.lastname: Ortmann
authors.forename: Alexander
authors.initials: A
authors.lastname: Kroemer
authors.forename: Gero
authors.initials: G
authors.lastname: Brockhoff
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology* / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019409:Interleukin-15