Characterization of the Genomic and Immunologic Diversity of Malignant Brain Tumors through Multisector Analysis
Maximilian O. Schaettler, Megan M. Richters, Anthony Z. Wang, Zachary L. Skidmore, Bryan Fisk, Katherine E. Miller, Tammi L. Vickery, Albert H. Kim, Michael R. Chicoine, Joshua W. Osbun, Eric C. Leuthardt, Joshua L. Dowling, Gregory J. Zipfel, Ralph G. Dacey, Hsiang‐Chih Lu, Tanner M. Johanns, Obi L. Griffith, Elaine R. Mardis, Malachi Griffith, Gavin P. Dunn
Abstract
Abstract Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy 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 profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole-exome, RNA, and T-cell receptor sequencing. Our analyses identified 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 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. Significance: This study describes the impact of spatial heterogeneity on genomic and immunologic characteristics of gliomas and brain metastases. The results suggest that gliomas harbor significantly greater intratumoral heterogeneity of genomic alterations, neoantigens, and T-cell clones than brain metastases, indicating the importance of multisector analysis for clinical or translational studies. This article is highlighted in the In This Issue feature, p. 1