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

in Cancer discovery by 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

TLDR

  • The study profiles the immunogenomic state of 30 malignant brain tumors, finding more spatial heterogeneity in gliomas compared to brain metastases.
  • The study suggests that gliomas have significantly greater intratumoral heterogeneity, with implications for targeted and immune-based therapies.
  • The findings highlight the importance of multisector analysis for clinical or translational studies of malignant brain tumors.

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..

Overview

  • The study explores the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors to understand the difference in spatial heterogeneity between primary gliomas and brain metastases.
  • The researchers profiled the tumors using whole-exome, RNA, and T-cell receptor sequencing to identify differences in genomic and neoantigen levels, as well as T-cell clones.
  • The study aims to define the immunogenomic landscape of malignant brain tumors and has implications for the design of targeted and immune-based therapies against intracranial malignancies.

Comparative Analysis & Findings

  • The study found that gliomas display more spatial heterogeneity at the genomic and neoantigen levels compared to brain metastases.
  • Gliomas harbored highly expanded but spatially restricted T-cell clones, which was not observed in brain metastases.
  • The study suggests that gliomas have significantly greater intratumoral heterogeneity of genomic alterations, neoantigens, and T-cell clones than brain metastases.

Implications and Future Directions

  • The study highlights the importance of multisector analysis for clinical or translational studies to understand the complex immunogenomic landscape of malignant brain tumors.
  • The findings could lead to the development of more effective targeted and immune-based therapies against primary gliomas and brain metastases.
  • Future studies could focus on validating the findings in larger patient cohorts and exploring potential therapeutic targets identified through this research.
Read Full Article