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

5.5 The Different MHC Class I Phenotypes and their Underlying Molecular Mechanisms
cally removed lesions, tumor cell lines of distinct histology also exhibit a heterogeneous
LMP2 and LMP7 expression pattern. Whether the changes of the LMP subunit
expression obtained in tumor lesions or tumor cell lines reflect a transformation-dependent
or tissue-specific regulation has not yet been determined. In addition,
expression of LMP10 as well as proteasome activator subunits PA28a and b
has been investigated in some tumor cell lines, but not in tumor lesions. LMP10 is
not constitutively expressed in most tumor cell lines analyzed. This deficiency is
frequently associated with the down-regulation of other APM components. In contrast,
PA28a and b appear to be comparably expressed in tumor and corresponding
normal cells.
Until now, little information has been available on the exact modalities of proteasomal
degradation and the specificity as well as the activity of cytosolic proteases in tumor
specimen. However, it appears to differ from that of professional APCs, thereby
resulting in the generation of a distinct set of antigenic peptides presented to CTLs
[55]. The abrogation of CTL epitope processing could also be attributable to single
amino acid substitutions in transforming genes [56, 57]. Thus, the expression pattern
of proteasome subunits in tumors might tune the generation of antigenic peptides
as well as the sensitivity to CTL-mediated lysis which could be further enhanced
by accelerated degradation of TAAs [56, 58]. These alterations may have important
implications on the success of T cell-based immunotherapies.
Although tapasin has been shown to play an important role in peptide loading of
MHC class Imolecules, thereby affecting both MHC class Isurface expression and
immune response, its involvement in immune escape has not been determined.
Seliger et al. [59] demonstrated deficient mRNA and protein expression of tapasin in
colon carcinoma and HNSCC which could be corrected by cytokine treatment. These
data were recently extended by Matsui et al. [60], providing evidence that the reduced
tapasin transcription and CTL-mediated lysis of hepatoma cells can be restored by tapasin
gene transfer.
A concomitant HLA class Iantigen and TAP down-regulation has been reported in
many tumors resulting in the generation of peptide-free, instable MHC class IHC/
b2-m heterodimers [59] (Fig. 5.10A). The frequency of TAP down-regulation or loss
varies from 10 to 84%, and is particularly high in primary and metastatic cervical
carcinomas. The altered frequencies of TAP deficiencies among different tumor
types may reflect differences in the characteristics of the patient populations investigated,
the immunobiology of various tumor types, the sensitivity of the immunohistochemical
methods used as well as changes in the proliferative status of the tumor
cells. Indeed, TAP1 expression might be regulated during the cell cycle. Only a few
lesions, in particular melanoma and breast carcinoma, have been analyzed for TAP2
protein expression. This is attributable to the lack of TAP2 mAbs which can be routinely
used on paraffin-embedded tissues. The frequency of TAP2 down-regulation
varied between the tumor types and tumor cell lines analyzed.
The extent of TAP1 and/or TAP2 down-regulation seems to be more pronounced in
metastatic than in primary lesions This has been shown in lesions obtained from cervical
carcinoma, RCC, HNSCC, colorectal carcinoma, breast carcinoma and uveal or
cutaneous melanoma [59, 61, 62] (Fig. 5.11). The impaired TAP expression in mela-
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