Engraftment of Human Glioblastoma Cells in Immunocompetent Rats through Acquired Immunosuppression.
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.
K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway; Centre for Immune Regulation, Department of Immunology, University of Oslo/the National Hospital, Oslo, Norway.
Peter C
PC
Huszthy
K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.
Per Ø
PØ
Sakariassen
K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.
Heidi
H
Espedal
Department of Clinical Science, University of Bergen, Bergen, Norway.
Karl A
KA
Brokstad
K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway; NorLux Neuro-Oncology Laboratory, CRP Santè, Luxembourg, Luxembourg.
Rolf
R
Bjerkvig
K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Hrvoje
H
Miletic
D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology*; D054357:Chemokine CXCL10 / Q000502:physiology; D054377:Chemokine CXCL12 / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007121:Immunocompetence / Q000276:immunology; D020382:Interleukin-18 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D009368:Neoplasm Transplantation / Q000379:methods*; D016133:Polymerase Chain Reaction; D051381:Rats; D011923:Rats, Nude; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
C575935:CXCL12 protein, rat; D054357:Chemokine CXCL10; D054377:Chemokine CXCL12; C091326:Cxcl10 protein, rat; D020382:Interleukin-18; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha