Abstract
Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Here, we generate distinct imageable syngeneic mouse GBM-tumor models and utilize RNA-sequencing, CyTOF and correlative immunohistochemistry to assess immune-profiles in these models. We identify immunologically-inert and -active syngeneic-tumor types and show that inert tumors have an immune-suppressive phenotype with numerous exhausted CD8 T cells and resident macrophages; fewer eosinophils and SiglecF+ macrophages. To mimic the clinical-settings of first line of GBM-treatment, we show that tumor-resection invigorates an anti-tumor response via increasing T cells, activated microglia and SiglecF+ macrophages and decreasing resident macrophages. A comparative CyTOF analysis of resected-tumor samples from GBM-patients and mouse GBM-tumors show stark similarities in one of the mouse GBM-tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients.
Highlights
Immunotherapy has emerged as a promising approach to treat cancer, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited
A number of preclinical studies assessing the efficacy of different therapeutics for GBM have focused on patient derived tumor models with the caveat that these xenografts can only grow in immune-compromised mice limiting their use in gaining new insights into the mechanisms associated with brain tumor immunotherapy-based research
Western blot analysis of lysates prepared from five lines: 005, CT2A, GL261, Mut[3], and Mut[4] confirmed that CT2A and GL261 have low levels of PTEN and high levels of p53 (Fig. 1b)
Summary
Immunotherapy has emerged as a promising approach to treat cancer, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. A number of preclinical studies assessing the efficacy of different therapeutics for GBM have focused on patient derived tumor models with the caveat that these xenografts can only grow in immune-compromised mice limiting their use in gaining new insights into the mechanisms associated with brain tumor immunotherapy-based research. Used GBM syngeneic tumor models are p53 WT/ PTEN deficient CT2A8 and K-ras mutant/p53 mutant GL2619 lines While both these tumor lines were generated by chemical induction with methylcholanthrene in C57BL/6 mice[10], there is a huge disparity in the number of studies performed on these two models. Mut 4 lines generated by inactivation of NF1 and p53 tumor suppressor genes with loss of PTEN16
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