Engraftment of Human Glioblastoma Cells in Immunocompetent Rats through Acquired Immunosuppression

PLoS One. 2015 Aug 20;10(8):e0136089. doi: 10.1371/journal.pone.0136089. eCollection 2015.

Abstract

Transplantation of glioblastoma patient biopsy spheroids to the brain of T cell-compromised Rowett (nude) rats has been established as a representative animal model for human GBMs, with a tumor take rate close to 100%. In immunocompetent littermates however, primary human GBM tissue is invariably rejected. Here we show that after repeated passaging cycles in nude rats, human GBM spheroids are enabled to grow in the brain of immunocompetent rats. In case of engraftment, xenografts in immunocompetent rats grow progressively and host leukocytes fail to enter the tumor bed, similar to what is seen in nude animals. In contrast, rejection is associated with massive infiltration of the tumor bed by leukocytes, predominantly ED1+ microglia/macrophages, CD4+ T helper cells and CD8+ effector cells, and correlates with elevated serum levels of pro-inflammatory cytokines IL-1α, IL-18 and TNF-α [corrected]. We observed that in nude rat brains, an adaptation to the host occurs after several in vivo passaging cycles, characterized by striking attenuation of microglial infiltration. Furthermore, tumor-derived chemokines that promote leukocyte migration and their entry into the CNS such as CXCL-10 and CXCL-12 are down-regulated, and the levels of TGF-β2 increase. We propose that through serial in vivo passaging in nude rats, human GBM cells learn to avoid and or/ suppress host immunity. Such adapted GBM cells are in turn able to engraft in immunocompetent rats without signs of an inflammatory response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / immunology*
  • Chemokine CXCL10 / physiology
  • Chemokine CXCL12 / physiology
  • Disease Models, Animal
  • Female
  • Glioblastoma / immunology*
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control*
  • Humans
  • Immune Tolerance / immunology*
  • Immunocompetence / immunology
  • Interleukin-18 / blood
  • Interleukin-1beta / blood
  • Male
  • Neoplasm Transplantation / methods*
  • Polymerase Chain Reaction
  • Rats
  • Rats, Nude
  • Spheroids, Cellular
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / blood

Substances

  • CXCL12 protein, rat
  • Chemokine CXCL10
  • Chemokine CXCL12
  • Cxcl10 protein, rat
  • Interleukin-18
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha

Grant support

Funding was provided by the Research Council of Norway, The Norwegian Cancer Society, Helse Vest, Haukeland University Hospital, the K.G. Jebsen Research Foundation and the Bergen Medical Research Foundation.