Mutant IDH1 regulates the tumor-associated immune system in gliomas

被引：309

作者：

Amankulor, Nduka M. ^{[1
]}

Kim, Youngmi ^{[2
]}

Arora, Sonali ^{[2
]}

Kargl, Julia ^{[2
,3
,4
]}

Szulzewsky, Frank ^{[2
]}

Hanke, Mark ^{[2
,3
]}

Margineantu, Daciana H. ^{[2
,3
]}

Rao, Aparna ^{[1
]}

Bolouri, Hamid ^{[2
,5
]}

Delrow, Jeff ^{[6
]}

Hockenbery, David ^{[2
,3
]}

Houghton, A. McGarry ^{[2
,3
,7
]}

Holland, Eric C. ^{[2
,5
]}

机构：

[1] Univ Pittsburgh, Dept Neurosurg, Pittsburgh, PA 15213 USA

[2] Fred Hutchinson Canc Res Ctr, Human Biol Div, Seattle, WA 98109 USA

[3] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA

[4] Med Univ Graz, Inst Expt & Clin Pharmacol, A-8010 Graz, Austria

[5] Fred Hutchinson Canc Res Ctr, Solid Tumor Translat Res, Seattle, WA 98109 USA

[6] Fred Hutchinson Canc Res Ctr, Genom & Bioinformat Shared Resources, Seattle, WA 98109 USA

[7] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA

来源：

GENES & DEVELOPMENT | 2017年 / 31卷 / 08期

关键词：

IDH mutation; immuno-oncology; glioma; NEURAL PROGENITORS; R PACKAGE; MUTATION; GROWTH; CLASSIFICATION; PROLIFERATION; GLIOBLASTOMAS; PROGRESSION; NEUTROPHILS; ACTIVATION;

D O I：

10.1101/gad.294991.116

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：774 / 786

页数：13

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