Immune landscape of isocitrate dehydrogenase-stratified primary and recurrent human gliomas

Pravesh Gupta, Minghao Dang, Shivangi Oberai, Simona Migliozzi, Rakesh Trivedi, Gayatri Kumar, Mekenzie Peshoff, Nancy Milam, Aml Ahmed, Krishna Bojja, Tuan M. Tran, Joy Gumin, Carlos Kamiya-Matsuoka, Jason Huse, Kathryn Cox, Jianzhuo Li, Huma Shehwana, Sameer A. Sheth, Rodriguez Saxon, Sun BaohuaBrittany Parker Kerrigan, Atul Maheshwari, Edwin Roger Parra Cuentas, Nicholas E. Navin, Amy B. Heimberger, Frederick F. Lang, Antonio Iavarone, Karen Clise-Dwyer, Linghua Wang, Krishna P. Bhat

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background. Human gliomas are classified using isocitrate dehydrogenase (IDH) status as a prognosticator; however, the influence of genetic differences and treatment effects on ensuing immunity remains unclear. Methods. In this study, we used sequential single-cell transcriptomics on 144 678 and spectral cytometry on over 2 million immune cells encompassing 48 human gliomas to decipher their immune landscape. Results. We identified 22 distinct immune cell types that contribute to glioma immunity. Specifically, brain-resident microglia (MG) were reduced with a concomitant increase in CD8+ T lymphocytes during glioma recurrence independent of IDH status. In contrast, IDH-wild type-associated patterns, such as an abundance of antigen-presenting cell-like MG and cytotoxic CD8+ T cells, were observed. Beyond elucidating the differences in IDH, relapse, and treatment-associated immunity, we discovered novel inflammatory MG subpopulations expressing granulysin, a cytotoxic peptide that is otherwise expressed in lymphocytes only. Furthermore, we provide a robust genomic framework for defining macrophage polarization beyond M1/M2 paradigm and reference signatures of glioma-specific tumor immune microenvironment (termed GlioTIME-36) for deconvoluting transcriptomic datasets. Conclusions. This study provides advanced optics of the human pan-glioma immune contexture as a valuable guide for translational and clinical applications.

Original languageEnglish (US)
Pages (from-to)2239-2255
Number of pages17
JournalNeuro-oncology
Volume26
Issue number12
DOIs
StatePublished - Dec 1 2024

Keywords

  • glioma
  • isocitrate dehydrogenase
  • microglia
  • tumor immune microenvironment

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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