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  • Poster presentation
  • Open Access

IDH mutation-induced suppression of type-1 anti-glioma immune response

  • 1,
  • 1,
  • 2,
  • 1,
  • 3 and
  • 1
Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P271

https://doi.org/10.1186/2051-1426-3-S2-P271

  • Published:

Keywords

  • Normal Human Astrocyte
  • Cell Base Immunotherapy
  • Normal Human Astrocyte Cell
  • CXCL10 Promotor
  • CXCL10 Expression Level

Isocitrate dehydrogenase (IDH) mutations are the first mutations that occur during the oncogenic process of lower-grade glioma (LGG) and confers a novel gain-of-function activity by converting α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), promoting DNA hyper-methylation. Our analysis of LGG cases from The Cancer Genome Atlas (TCGA) database revealed that IDH-mutant (IDH-Mut) cases exhibit decreased expression of type-1 effector T cell response-related genes, which are critical for anti-glioma immunity, including: CD8A, IFNG, OAS2, GZMA, EOMES, CXCL9 and CXCL10, compared with IDH-wild type (IDH-WT) cases. On the other hand, type-2 and regulatory T cell response-related genes, such as IL5 and TGFB1, are not significantly different between IDH-Mut vs. WT cases, indicating that the observed down-regulation of type-1 response-related genes does not merely represent a possible global gene suppression. Furthermore, IDH-Mut cases exhibit increased CXCL10 promotor methylation compared with WT cases. We thus hypothesized that IDH mutation-mediated tumor intrinsic mechanisms occurring within glioma cells may inhibit anti-tumor immunity to promote tumor growth. In vitro, a normal human astrocyte (NHA) cell line transfected with IDH1-Mut cDNA expressed lower levels of CXCL10 compared to NHA cells transfected with WT IDH1. Consistently, C57Bl/6 mouse-syngeneic astrocyte and glioma cell lines transfected with IDH1-Mut expressed lower levels of CXCL10 gene and protein, compared to control cells transfected with IDH-WT, which was restored following 30 day treatment of the cells with the IDH1 inhibitor, IDH-C35. Furthermore, in vivo orthotopic IDH1-Mut gliomas at 21 days post-intracranial injection in syngeneic mice expressed lower levels of T cell chemokines CXCL9 and CXCL10 as determined by RT-PCR and ELISA and reduced infiltration of CD3+CD8+ T cells as determined by flow cytometry and quantitative immunohistochemistry compared with control IDH1-WT gliomas. Further, an in vitro migration assay demonstrated reduced migration of T cells towards culture supernatants from IDH1-Mut cell lines compared with control supernatants derived from IDH1-WT cells. Overall, our data demonstrate that IDH mutations in tumor cells lead to reduced T cell attracting chemokines and reduced T cell accumulation in gliomas. Our analyses of the TCGA 450K gene methylation database suggest that the suppressed expression of OAS2 and CXCL10 in IDH1-Mut cases is associated with hypermethylation of the promoter for these genes. Indeed, treatment of IDH-Mut cell lines with demethylating agent 5-Aza-CdR restored CXCL10 expression levels. Our data suggest that IDH inhibitors and demethylation agents may be used to enhance T cell recruitment to LGG in combination with T cell based immunotherapies.

Authors’ Affiliations

(1)
University of California, San Francisco, San Francisco, CA, USA
(2)
University of Pittsburgh, Pittsburgh, PA, USA
(3)
University of California San Francisco, San Francisco, CA, USA

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