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* Department of Neurology, Medical School, and
Institute of Brain Research, University of Tübingen, Tübingen, Germany; and
Institute of Anthropology and Human Genetics, Ludwig Maximilians University, Munich, Germany
HLA-G is a nonclassical MHC molecule with highly limited tissue
distribution that has been attributed chiefly immune regulatory
functions. Glioblastoma is paradigmatic for the capability of human
cancers to paralyze the immune system. To delineate the potential role
of HLA-G in glioblastoma immunobiology, expression patterns and
functional relevance of this MHC class Ib molecule were investigated in
glioma cells and brain tissues. HLA-G mRNA expression was detected in
six of 12 glioma cell lines in the absence of IFN-
and in 10 of 12
cell lines in the presence of IFN-. HLA-G protein was detected in
four of 12 cell lines in the absence of IFN- and in eight of 12 cell
lines in the presence of IFN-. Immunohistochemical analysis of human
brain tumors revealed expression of HLA-G in four of five tissue
samples. Functional studies on the role of HLA-G in glioma cells were
conducted with alloreactive PBMCs, NK cells, and T cell
subpopulations. Expression of membrane-bound HLA-G1 and soluble
HLA-G5 inhibited alloreactive and Ag-specific immune responses. Gene
transfer of HLA-G1 or HLA-G5 into HLA-G-negative glioma cells (U87MG)
rendered cells highly resistant to direct alloreactive lysis, inhibited
the alloproliferative response, and prevented efficient priming of
cytotoxic T cells. The inhibitory effects of HLA-G were directed
against CD8 and CD4 T cells, but appeared to be NK cell independent.
Interestingly, few HLA-G-positive cells within a population of
HLA-G-negative tumor cells exerted significant immune inhibitory
effects. We conclude that the aberrant expression of HLA-G may
contribute to immune escape in human
glioblastoma.
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