Characterization of the Genomic and Immunological Diversity of Malignant Brain Tumors Through Multi-Sector Analysis

Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). While the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer-cell intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole exome, RNA, and TCR-sequencing. Our analyses identified differences between primary and secondary malignancies with gliomas displaying more spatial heterogeneity at the genomic and neoantigen level. Additionally, this spatial diversity was recapitulated in the distribution of T cell clones where some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies.