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-1β, IL-18 and TNF-α. 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.
Highlights
When evaluating therapeutic approaches to be implemented in clinical oncology, using animal models with high relevance to human tumors is essential
We show that human GBM tissue serially passaged in nude rat brains may engraft in immunocompetent littermates in contrast to spheroids made directly from patient biopsies
Human glioblastoma xenograft engraftment in immunocompetent rats We transplanted biopsy spheroids derived from six patients diagnosed with primary GBM to the right hemisphere of immunocompetent and nude rats
Summary
When evaluating therapeutic approaches to be implemented in clinical oncology, using animal models with high relevance to human tumors is essential. We have previously established and characterized a patient biopsy xenograft model of glioblastoma multiforme in T cell-compromised nude rats, which has been applied in several studies of basic- and translational neuro-. Human Glioblastoma Engraftment in Immunocompetent Rats oncology [1,2,3,4,5,6,7], reviewed in [8] In this model, the tumor tissue is mechanically dissociated and adapted to agar-overlay cultures to allow the formation of spheroids between each in vivo passaging stage. Tumor cells in syngeneic models generally fail to show diffuse infiltration into the host brain, which is a prominent hallmark of human GBMs. the establishment of an infiltrative GBM model based on human xenograft material growing in immunocompetent animals would be desirable. The mechanisms that govern GBM xenograft tolerance in rodents have not been well characterized; most of our knowledge relating to tissue engraftment in the rat CNS derives from transplantation experiments aimed at correcting neurodegenerative disorders [14]
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