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

ples were derived from either primary cancers or metastases from more than 30 different
tumor types. MHC class Ialterations appear to occur at a particular step in progression
from benign to most aggressive tumors, demonstrating a gradient of expression
between normal cells, primary tumors and tumor metastases. Depending on the tumor
type analyzed, a loss of MHC class Iantigens of 9±52%, an antigen down-regulation
of 3±20%, and a selective allele-specific loss or down-regulation varying between
15 and 50% was found. In the following section, the underlying molecular mechanisms
of the distinct HLA class Iphenotypes are discussed.
5.5.1
MHC Class I Loss
5.5 The Different MHC Class I Phenotypes and their Underlying Molecular Mechanisms
Loss of MHC class Iantigens is found in 15% of melanomas, 9% of head and neck
carcinomas, and 21% of colorectal tumors [44]. In prostate and breast carcinomas,
MHC class Iloss varies between 34 and 52%, respectively. Although a variety of molecular
mechanisms contribute to this phenotype, it is mainly caused by structural
defects in one copy of the b2-m gene. This is associated with the loss of the wild-type
b 2-m allele (Fig. 5.7 and Tab. 5.1). The latter is either attributable to a mitotic recombination
event or to the loss of chromosome 15, on which the b2-m gene is located
[45]. This phenotype is consistent with the loss of heterozygosity (LOH) frequently
detected in tumor cells due to their genetic instability [46]. Lack of HLA class Iantigen
expression can be corrected by transfection of cells with the wild-type b2-m gene
or cDNA [47±49]. This reflects the inability of b2-m free HLA class IHC to travel
through the trans-Golgi apparatus to the cell surface.
The mutations in the b2-m gene described in the literature include base pair (bp)
substitutions and deletions which range from loss of 1 bp to loss of extensive segments
of the gene (Tab. 5.1 and Fig. 5.8). The mutations are randomly distributed
through the leader sequences, exon 1, intron 1 and exon 2. In contrast, a dinucleotide
CT deletion in an 8-bp CT repeat region in exon 1 appears to represent a mutation
ªhot spotº within the b2-m gene, since the dinucleotide CT deletion has been
Fig. 5.7 Loss of MHC class I surface expression due to structural
alterations of the b2-m gene. Structural alterations in the
b2-m associated with the loss of one copy of the b2-m gene
causes lack of MHC class I surface expression. Such defects
occur at a high frequency in some tumor entities due to deficient
HC/b2-m dimer formation.
67