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Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12823-8. doi: 10.1073/pnas.1413933111. Epub 2014 Aug 18.

Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients.

Author information

1
Departments of Neurological Surgery.
2
Pathology.
3
Seattle Children's Research Institute, Seattle, WA 98101;
4
Kalmanovitz Liver Immunology Laboratory, California Pacific Medical Center and Research Institute, San Francisco, CA 94115; and.
5
Medicine.
6
Surgery, and.
7
Kalmanovitz Liver Immunology Laboratory, California Pacific Medical Center and Research Institute, San Francisco, CA 94115; and Division of Hepatology, California Pacific Medical Center and Sutter Pacific Medical Foundation, San Francisco, CA 94115.
8
Microbiology, University of California, San Francisco, CA 94143; lewis.lanier@ucsf.edu.

Abstract

Myeloid cells are key regulators of the tumor microenvironment, governing local immune responses. Here we report that tumor-infiltrating myeloid cells and circulating monocytes in patients with glioblastoma multiforme (GBM) express ligands for activating the Natural killer group 2, member D (NKG2D) receptor, which cause down-regulation of NKG2D on natural killer (NK) cells. Tumor-infiltrating NK cells isolated from GBM patients fail to lyse NKG2D ligand-expressing tumor cells. We demonstrate that lactate dehydrogenase (LDH) isoform 5 secreted by glioblastoma cells induces NKG2D ligands on monocytes isolated from healthy individuals. Furthermore, sera from GBM patients contain elevated amounts of LDH, which correlate with expression of NKG2D ligands on their autologous circulating monocytes. NKG2D ligands also are present on circulating monocytes isolated from patients with breast, prostate, and hepatitis C virus-induced hepatocellular carcinomas. Together, these findings reveal a previously unidentified immune evasion strategy whereby tumors produce soluble factors that induce NKG2D ligands on myeloid cells, subverting antitumor immune responses.

KEYWORDS:

LDH5; cancer; glioma; tumor evasion

PMID:
25136121
PMCID:
PMC4156766
DOI:
10.1073/pnas.1413933111
[Indexed for MEDLINE]
Free PMC Article

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