Immune landscape of a genetically engineered murine model of glioma compared with human glioma
Daniel B Zamler1,2,3, Takashi Shingu2, Laura M Kahn3,4
1Department of Genomic Medicine.
Abstract:
Novel therapeutic strategies targeting glioblastoma (GBM) often fail in the clinic, partly because preclinical models in which hypotheses are being tested do not recapitulate human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/Trp53/Pten (QPP) triple-knockout model of human GBM, comparing the immune microenvironment of QPP mice with that of patient-derived tumors to determine whether this model provides opportunity for gaining insights into tumor physiopathology and preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice and from patients with glioma revealed intratumoral immune components that were predominantly myeloid cells (e.g., monocytes, macrophages, and microglia), with minor populations of T, B, and NK cells. When comparing spontaneous and implanted mouse samples, we found more neutrophils and T and NK cells in the implanted model. Neutrophils and T and NK cells were increased in abundance in samples derived from human high-grade glioma compared with those derived from low-grade glioma. Overall, our data demonstrate that our implanted and spontaneous QPP models recapitulate the immunosuppressive myeloid-dominant nature of the tumor microenvironment of human gliomas. Our model provides a suitable tool for investigating the complex immune compartment of gliomas.
Insights
Preclinical glioblastoma (GBM) models often fail to mimic human disease. Our QPP mouse model effectively recapitulates the immunosuppressive, myeloid-dominant tumor microenvironment of human gliomas, offering a valuable tool for therapeutic development.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Novel glioblastoma (GBM) therapies frequently fail in clinical trials due to limitations in preclinical models.
- Existing models may not accurately reflect the complex human disease, hindering the development of effective treatments.
Purpose of the Study:
- To evaluate a novel Qk/Trp53/Pten (QPP) triple-knockout mouse model for its ability to recapitulate the human GBM immune microenvironment.
- To assess the suitability of the QPP model for preclinical testing of therapeutic agents targeting GBM.
Main Methods:
- Immune profiling and single-cell sequencing were performed on spontaneous and implanted tumors from QPP mice.
- Tumor immune microenvironments were compared between QPP mouse models and patient-derived glioma samples.
Main Results:
- Both QPP mouse models (spontaneous and implanted) and human gliomas exhibit a myeloid-dominant immune microenvironment, characterized by monocytes, macrophages, and microglia.
- Implanted QPP models showed increased neutrophils and T/NK cells compared to spontaneous models.
- Human high-grade gliomas had higher neutrophil and T/NK cell abundance than low-grade gliomas.
Conclusions:
- The QPP mouse model accurately recapitulates the immunosuppressive, myeloid-rich tumor microenvironment characteristic of human gliomas.
- This validated model serves as a powerful tool for investigating glioma immunobiology and evaluating novel therapeutic strategies.
