Immune landscape-based machine-learning–assisted subclassification, prognosis, and immunotherapy prediction for glioblastoma

INTRODUCTION: As a malignant brain tumor, glioblastoma (GBM) is characterized by intratumor heterogeneity, a worse prognosis, and highly invasive, lethal, and refractory natures. Immunotherapy has been becoming a promising strategy to treat diverse cancers. It has been known that there are highly heterogeneous immunosuppressive microenvironments among different GBM molecular subtypes that mainly include classical (CL), mesenchymal (MES), and proneural (PN), respectively. Therefore, an in-depth understanding of immune landscapes among them is essential for identifying novel immune markers of GBM. METHODS AND RESULTS: In the present study, based on collecting the largest number of 109 immune signatures, we aim to achieve a precise diagnosis, prognosis, and immunotherapy prediction for GBM by performing a comprehensive immunogenomic analysis. Firstly, machine-learning (ML) methods were proposed to evaluate the diagnostic values of these immune signatures, and the optimal classifier was constructed for accurate recognition of three GBM subtypes with robust and promising performance. The prognostic values of these signatures were then confirmed, and a risk score was established to divide all GBM patients into high-, medium-, and low-risk groups with a high predictive accuracy for overall survival (OS). Therefore, complete differential analysis across GBM subtypes was performed in terms of the immune characteristics along with clinicopathological and molecular features, which indicates that MES shows much higher immune heterogeneity compared to CL and PN but has significantly better immunotherapy responses, although MES patients may have an immunosuppressive microenvironment and be more proinflammatory and invasive. Finally, the MES subtype is proved to be more sensitive to 17-AAG, docetaxel, and erlotinib using drug sensitivity analysis and three compounds of AS-703026, PD-0325901, and MEK1-2-inhibitor might be potential therapeutic agents. CONCLUSION: Overall, the findings of this research could help enhance our understanding of the tumor immune microenvironment and provide new insights for improving the prognosis and immunotherapy of GBM patients.