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

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5 Major Histocompatibility Complex Modulation and Loss
vels too low for detection or by post-transcriptional down-regulation. These conflicting
results are not unique for melanoma, since controversial findings have also been
described in other types of malignancies [140].
5.9.2
Clinical Impact of HLA-G Expression
In lung carcinoma, HLA-G protein expression correlated with both the histological tumor
type and grade [138]. Paul et al. [133] reported HLA-G protein expression in cell
lines and in biopsies derived from primary and metastatic melanoma lesions. Thus,
HLA-G expression represents an early event in melanoma progression. HLA-G transcript
levels in tumor regression sites were comparable to those in healthy skin, suggesting
an association between HLA-G expression and disease progression. A similar
conclusion has been reached by Wagner et al. [141] who investigated 10 patients with
melanoma prior to treatment with high-dose IFN-a2 b. Immunohistochemical staining
and SDS±PAGE analysis of antigens immunoprecipitated with a rabbit anti-HLA-
G serum detected HLA-G antigens in five metastases all of which had lost classical
HLA class Iantigen expression. This phenotype was associated with relapse of the disease
within the first six months of treatment. Wagner et al. [141] have suggested that
the unresponsiveness to therapy with IFN-a2b was caused by escape of melanoma
cells from CTL recognition because of classical HLA class Iantigen loss and by protection
from NK cell recognition because of HLA-G expression.
5.9.3
Induction of Tolerance by HLA-G Expression
Tumors with deficient MHC class Iexpression consequently become targets for NK
cell-mediated lysis. Despite abnormalities in the surface expression of classical MHC
class Iantigens, most tumors grow in vivo, suggesting an additional escape of NK
cell attack. The absence of a single HLA class Iallele is sufficient for the activation of
a particular NK cell population bearing the NK inhibitory receptor KIR. The nonclassical
HLA-G molecules inhibit NK lytic activity upon interaction with KIRs,
thereby establishing a powerful mechanism of tumors to escape NK cell-mediated
tumor immune surveillance. Thus, the role of HLA-G antigens in the interaction of
CTLs and NK cells with target cells and the aberrant expression of these molecules
by malignant cells have provided the impetus to characterize the expression of HLA-
G antigens in malignant lesions and their clinical significance [43].
5.10
Conclusions
The information we have reviewed clearly indicates that distinct molecular lesions
underlie abnormalities in the expression of classical MHC class Ias well as MHC
class II antigens identified in malignant cells. Although the available information is