Mutant IDH1 regulates the tumor-associated immune system in gliomas
- Nduka M. Amankulor1,
- Youngmi Kim2,
- Sonali Arora2,
- Julia Kargl2,3,4,
- Frank Szulzewsky2,
- Mark Hanke2,3,
- Daciana H. Margineantu2,3,
- Aparna Rao1,
- Hamid Bolouri2,5,
- Jeff Delrow6,
- David Hockenbery2,3,
- A. McGarry Houghton2,3,7 and
- Eric C. Holland2,5
- 1Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA;
- 2Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
- 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
- 4Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria 8010;
- 5Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
- 6Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
- 7Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington 98195, USA
- Corresponding author: eholland{at}fredhutch.org
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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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.294991.116.
- Received December 19, 2016.
- Accepted April 12, 2017.
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