Characterization of the Genomic and Immunologic Diversity of Malignant Brain Tumors through Multisector Analysis

Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited effi cacy against primary brain malignancies such as glioblastoma (GBM). Although 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 profi led the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through wholeexome, RNA, and T-cell receptor sequencing. Our analyses identifi ed differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defi nes 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.