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

5.5 The Different MHC Class I Phenotypes and their Underlying Molecular Mechanisms
identified in approximately 30 % of cell lines analyzed with HLA class Iantigen loss
(Tab. 5.1) [50]. This possibility is supported by the higher susceptibility of such nucleotide
elements to defective DNA repair mechanisms, and by the association found
between the lack of a functional b2-m and the presence of a mutator phenotype in a
panel of 37 colon carcinoma cell lines [51].
Most of the b2-m mutations inhibit their translation rather than their transcription.
This mechanism explains the lack of functional b2-m protein in spite of the apparently
normal b2-m mRNA levels in the majority of the cell lines analyzed which do
not express HLA class Iantigens. Deficient b2-m protein expression results in a failure
to express trimeric peptide/HC/b2-m complexes at the cell surface. Thus, screening
of surgically removed tumor lesions and tumor cell lines for functional b2-m expression
should be performed by Western blot, flow cytometry and/or immunohistochemical
staining using anti-b2-m antibodies.
The frequency of b2-m mutations markedly differs among various types of malignancies.
These mutations have been found frequently in colon carcinoma and melanoma,
but rarely in other types of malignancies, such as head and neck squamous
cell carcinoma (HNSCC), renal cell carcinoma (RCC), and cervical carcinoma [42,
44]. The reason(s) for these differences remain(s) to be determined.
5.5.2
MHC Class I Down-regulation
The molecular mechanisms causing down-regulation of MHC class Iantigens have
been demonstrated to be quite heterogeneous. Many of them can be corrected by
IFN-g treatment. Altered binding of regulatory factors to the MHC class IHC gene
enhancer element by methylation or changes in the chromatin structure results in
MHC class IHC mRNA down-regulation and consequently in a reduced expression
of these molecules on the cell surface (Fig. 5.9) [52, 53].
An alternative mechanism is represented by defects in the peptide loading of HLA
class Iantigens, resulting in impaired assembly and stability of MHC class Imolecules.
This is caused by abnormalities in the expression and/or function of different
component(s) of the MHC class Iantigen-processing and -presentation pathway,
such as the proteasomal subunits LMP2, LMP7 and LMP10, the peptide transporter
TAP, and the chaperone tapasin [54] (Fig. 5.10 and Tab. 5.2).
So far, the expression of the proteasome subunits has only been determined in a
limited number of surgically removed tumor lesions and tumor cell lines of dis-
Fig. 5.9 Down-regulation of
MHC class I surface expression
due to deficient MHC class I HC
expression.
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