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

5.5 The Different MHC Class I Phenotypes and their Underlying Molecular Mechanisms
Fig. 5.14 LOH in a colon carcinoma lesion. The electropherogram
profile obtained with the D6S311 microsatellite
marker in lymphocyte (L), microdissected stroma
(S), tumor tissue (T) and microdissected tumor (DT)
shows that the signal obtained in one allele is reduced
and almost undetectable when DNA obtained from the
tumor and from the microdissected tumor, respectively,
is used.
tail, although chromosomal loss has been identified in 14±17% of melanoma, colon
and laryngeal carcinoma, respectively. However, these results appear to be underestimated
since the heterogeneity of tumor tissues as well as its contamination with
stroma cells decreases the detection level of LOH.
Two mechanisms have been described to underlie the down-regulation of the gene
products of one HLA locus which appears to be more frequent for HLA-B than for
HLA-A antigens (Fig. 5.15A). An inverse association has been reported between
HLA locus antigen down-regulation and over-expression of various oncogenes, such
as c-myc, HER-2/neu and ras [73, 74], which interfere with the HLA locus transcription
at the promoter level. An additional mechanism is represented by the loss of
transcription factor binding to HLA locus-specific regulatory elements as particularly
demonstrated in colon cancer cells [75].
Like the selective down-regulation of HLA-A or -B antigens in defined tumor types,
HLA class Iallele-specific loss is not unique for malignant cells, since both of them
have also been found in normal cells [76]. The employment of a large series of mAbs
directed against specific alleles identified a MHC class Iallele-specific loss in many
tumors with a frequency ranging from 15 to 51%, which is higher than other HLA
class Iabnormalities (Fig. 5.15B). It is caused by mutations in the genes encoding
HLA class IHC including base pair insertions and base pair substitutions in exons
or introns and partial deletion as a consequence of chromosomal breakage or somatic
recombination (Tab. 5.4). The available information is not sufficient to determine
whether hot spot mutations are present in any of the HLA class Ialleles or
whether the mutations occur randomly. Further studies are also required to determine
whether mutations in HLA class IHC vary among malignant diseases.
75