Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

plays a central role in promoting tumor surveillance. This could either be due to a direct
effect of IFN-g by enhancing MHC class Iand/or IIantigen processing or presentation
on tumor cells or due to indirect effects of IFN-g, such as activation of NK cells,
macrophages and neutrophils, and antiangiostatic actions [163]. However, there also
exist physiological alternative IFN-gR signaling pathways, but their consequences on
the host antitumor response has still to be evaluated [125].
5.8.2
Deficiencies in the IFN Signal Transduction Pathway
5.9 HLA-G Expression: an Immune Privilege for Malignant Cells? 85
The deficient inducibility of components of the MHC class Iand IIantigen processing
and presentation pathway can be due to either structural alterations of the
IFNRs and factors involved in the modulation of IFN responses or dysregulation of
components of the IFN signal transduction pathway.
Human tumors with mutations inactivating different components of the IFN-g signal
transduction pathway selectively become insensitive to IFN-g treatment [120]. At
present, only a few mutations in IRFs have been identified. Inactivation of IRF1 and
IRF2 by point mutations or deletions was found in gastric cancer, leukemias and preleukemic
myelodysplasias as well as pancreatic carcinomas, respectively [91, 126±
128]. These structural alterations result in a markedly reduced DNA binding activity
as well as transactivating capacity. The effects of these mutations on other IFN-regulated
genes are unknown. Since only a few mutations have been identified so far,
further studies will be necessary to determine the frequency of these mutations and
their effect on tumor-related phenotypes, e. g. resistance to apoptosis, as well as
whether they also occur in other tumor specimens [129].
The unresponsiveness to IFN could also be accounted to dysregulation of the JAK/
STAT1 signaling. A link between defects in STAT1 phosphorylation or in the lack of
binding activity to IFRs elements causing STAT1 protein deficiencies and the failure
to up-regulate MHC class Isurface expression has been demonstrated in MCA-induced
tumors as well as gastric adenocarcinomas, respectively [130, 131].
5.9
HLA-G Expression: an Immune Privilege for Malignant Cells?
Altered patterns of MHC class Isurface expression in tumors have been shown to affect
the capacity of CTL and NK cells to generate cytotoxic responses against tumor
cells in vitro [26, 27]. The non-classical MHC class Iantigens HLA-G and -E have recently
been described as inhibitors of immune responses [43] as they inhibit CTL- as
well as NK cell-mediated lysis. Furthermore, HLA-G plays a key role in establishing
the feto-maternal tolerance during pregnancy. The potential impact of non-classical
MHC class Iantigen expression is currently under investigation. The data received
so far suggest that the consequence of HLA-G expression in malignant cells is the escape
of tumors from immunosurveillance.