Mutant IDH1 Regulates the Tumor-associated Immune System in Gliomas

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2017 May 4

PMID 28465358

Citations 233

Authors

Nduka M Amankulor

Youngmi Kim

Sonali Arora

Julia Kargl

Frank Szulzewsky

Mark Hanke

Daciana H Margineantu

Aparna Rao

Hamid Bolouri

Jeff Delrow

David Hockenbery

A McGarry Houghton

Eric C Holland

Affiliations

Soon will be listed here.

Abstract

Gliomas harboring mutations in isocitrate dehydrogenase 1/2 (IDH1/2) have the CpG island methylator phenotype (CIMP) and significantly longer patient survival time than wild-type IDH1/2 (wtIDH1/2) tumors. Although there are many factors underlying the differences in survival between these two tumor types, immune-related differences in cell content are potentially important contributors. In order to investigate the role of IDH mutations in immune response, we created a syngeneic pair mouse model for mutant IDH1 (muIDH1) and wtIDH1 gliomas and demonstrated that muIDH1 mice showed many molecular and clinical similarities to muIDH1 human gliomas, including a 100-fold higher concentration of 2-hydroxygluratate (2-HG), longer survival time, and higher CpG methylation compared with wtIDH1. Also, we showed that IDH1 mutations caused down-regulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system. Given that significant infiltration of immune cells such as macrophages, microglia, monocytes, and neutrophils is linked to poor prognosis in many cancer types, these reduced immune infiltrates in muIDH1 glioma tumors may contribute in part to the differences in aggressiveness of the two glioma types.

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