An immunocompetent mouse model of human glioblastoma

Abstract

Orthotopic xenotransplantation studies represent the final stage in preclinical cancer research and could facilitate the implementation of precision medicine. To date, these xenografts have been tested in immunodeficient animals, but complete elimination of the adaptive immunity is a significant drawback. We present a method of efficient human glioblastoma (GBM) cell engraftment in adult mice with intact immune systems, mediated by a transient blockade of T-cell co-stimulation. Compared to transplants grown in immunodeficient hosts, the resulting tumors more accurately resemble the clinical pathophysiology of patient GBMs, which are characterized by blood-brain-barrier leakage and strong neo-vascularization. We expect our method to have great utility for studying human tumor cell biology, particularly in the field of cancer immunotherapy and in studies on microenvironmental interactions. Given the straightforward approach, the method may also be applicable to other tumor types and additional model organisms.

Metastatic breast cancer cells induce altered microglial morphology and electrical excitability in vivo

“…However, the number of intact breast cancer cells was dramatically reduced after 5 days, although we could still detect isolated DsRed-positive cells and punctate acellular DsRed fluorescence at the lesion site at the end of the experiment. This rapid clearance of the tumour cells may reflect, in part, a graft versus host immune response to the xenotransplantation of a human breast cancer cell line into an immunocompetent mouse [51], although there was very limited infiltration of CD45 hi immune cells at the lesion site. An alternative possibility is that the DsRed cells rapidly die by necrosis or apoptosis, although the significant disruption to the local architecture of the cortical parenchyma in the presence of the cancer cells would argue against this.…”

Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts

“…This is highly significant as it allows studying behavior of human cells in various available transgenic mouse models or disease systems where adaptive immunity plays important role such as stroke or multiple sclerosis. We have recently shown that similar strategy with CoB can be used for modeling F o r P e e r R e v i e w human glioblastoma in immunocompetent mice (Semenkow et al, 2017) further demonstrating universal utility of this method.…”

Patient-derived xenograft models in musculoskeletal malignancies

“…The novel gene editing technology CRISPR-Cas9 could also be applied for the development of humanized mice models by substitute part of the mouse gene with a particular gene of human origin to express functional components of the human immune system [ 90 ], such as PD-1/PD-L1, thus enabling the testing of some immune-targeting agents. Instead of constructing murine models with intact human immune systems, some studies have reported their success in generating xenograft models by transplanting human tumor cell lines into immunosuppressed or immunotolerant mice to construct xenografts with intact murine immune systems [ 91 , 92 ]. Using this approach to establish immunocompetent PDX models may be a promising strategy to optimize current immunodeficient models.…”