CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: Glioblastoma (GBM) is the deadliest primary brain tumor in adults, where current therapies fail to extend survival meaningfully. Available animal GBM tumor models, especially therapy-resistant and recurrent models with human tumor and human immune cell interactions, are limited, impeding innovative treatment research. To address this critical obstacle, we established a unique GBM mouse model using patient-derived xenografts (PDXs) in humanized mice. METHODS: We selected 2 immunodeficient mouse models that express key human cytokines required for the proper reconstitution of myeloid lineage cells. After undergoing myeloablation, mice received CD34+ hematopoietic stem progenitor cells derived from human umbilical cord blood for humanization. Upon confirming the reconstitution of human blood cells, mice were xenografted with radiation-resistant PDXs. Tumor profiles and immune cell infiltration were analyzed via spectral flow cytometry, immunohistochemistry, and single-cell RNA sequencing (scRNA-seq). The results were benchmarked against scRNA-seq data from patients with recurrent human GBM. RESULTS: A diverse range of human immune cells, including T cells, natural killer cells, and myeloid lineage cells, infiltrated PDX tumors in humanized mice. Notably, gene expression profiles in these immune cells resembled those of recurrent human GBM. Unlike conventional xenograft models, this model highlighted enhanced tumor diversity, particularly a high fraction of neural progenitor-like cells. CONCLUSIONS: Our humanized GBM mouse model exhibited an immune cell signature similar to that of human recurrent GBM. This model is a valuable resource for analyzing the tumor immune landscape and assessing new therapies, particularly immunotherapies. Glioblastoma remains the most lethal brain tumor partly because current animal models fail to reproduce the complexity of the human immune system, hindering drug development. Addressing this, we developed a novel mouse model by implanting therapy-resistant patient-derived glioblastoma cells into humanized mice with a functional human immune system. This advanced model closely recapitulated the immunosuppressive tumor microenvironment and pronounced heterogeneity of human recurrent glioblastoma. Our findings suggest that this platform enables more accurate evaluation of emerging treatments, particularly immunotherapies, in a human immune cell context and may help accelerate the development of effective therapies for deadly brain tumors.