Humanized Tumor Mice--A New Model to Study and Manipulate the Immune Response in Advanced Cancer Therapy

Int J Cancer. 2011 Nov 1;129(9):2194-206. doi: 10.1002/ijc.26159. Epub 2011 Jul 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / therapy*
  • Cell Line, Tumor
  • Disease Models, Animal*
  • Female
  • Graft Rejection / immunology
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Interleukin-15 / immunology
  • Interleukin-15 / pharmacology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Mice*
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • T-Lymphocytes / immunology

Substances

  • Interleukin-15