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

somal antigen-processing machinery seems to be a widespread phenomenon, so far
there exists no experimental evidence that this has any significant functional consequences
for the processing of tumor antigens, since the vast majority of epitopes will
also be generated by constitutive proteasomes.
3.3.1
Impaired Epitope Generation by Immuno-Proteasomes
Morel et al. [32] recently reported that immuno-proteasomes are unable to produce
several self-antigen-derived CTL epitopes, including an important CTL epitope derived
from the melanoma differentiation antigen, Melan-A. These data represent the
first example of CTL epitopes that are generated by constitutive but not by immunoproteasomes
and may have a large impact on our understanding of tumor immunology.
Since it is likely that thymic dendritic cells involved in T cell selection predominantly
contain immuno-proteasomes, it was suggested that this observations could
explain how CTLs against self-antigens escape destruction in the thymus. These T
cells could be recruited for tumor therapy using vaccination strategies. Although this
seems to be an interesting hypothesis, further studies involving more tumor-derived
CTL epitopes will be required to elucidate the underlying molecular mechanism and
how CTLs specific for self-antigens can survive negative selection in the thymus.
Biochemical analysis of stimulated dendritic cells (DC) shows that during maturation
of DCs the synthesis of immuno-proteasomes increases and that at day 6 most
of the newly synthesized proteasomes are immuno-proteasomes [38]. Nevertheless,
considering the long half-live of proteasomes, DCs still ought to contain a considerable
amount of constitutive proteasomes even at day 6 after stimulation. Thus upregulation
of immuno-proteasomes may not be the only explanation for impaired tumor
epitope processing. In fact, in our own studies of melanoma cells we identified
a tyrosinase-related protein 2 (TRP2)-derived epitope whose presentation diminishes
upon treatment of melanoma cells with IFN-g. However, this reduction of antigenic
peptide presentation was found on all IFN-g-treated melanoma cells, including one
cell line which lacks constitutive expression of immuno-proteasomes and PA28, and
in which immuno-subunit and PA28 expression are not up-regulated following IFNg
treatment. These data indicate that there must exist other IFN-g inducible factors
which can negatively influence tumor epitope presentation and which are distinct
from immuno-proteasomes or even the proteasome system.
3.4
PA28 and Tumor Epitope Processing
3.4 PA28 and Tumor Epitope Processing
Under non-inflammatory conditions many cell types lack immuno-subunit expression
and express PA28ab only at low levels. One plausible explanation for the apparent
necessity to regulate immuno-subunit and PA28 expression may lie in their possible
role in the development of the CD8 T cell repertoire. In particular, the observation
that immuno-subunits may influence antigen processing of foreign and self-
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