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

72 5 Major Histocompatibility Complex Modulation and Loss
noma directly correlates with reduced recognition of metastatic tumor cells by autologous
TAA-specific CTLs [63]. The clinical relevance of this observation has only been
evaluated in melanoma, demonstrating that TAP down-regulation is associated with
reduced patient survival [61, 62, 64] (Fig. 5.12). Thus, down-regulation or loss of TAP1
and TAP2 appear to represent an independent prognostic marker for melanoma [64].
TAP down-regulation can frequently be corrected by IFN-g,whereas TAP deficiencies
are mainly caused by dysregulation. However, loss of its IFN-g inducibility can also be
caused by structural alterations in the peptide transporter subunits or by defects in the
early steps of the IFN-g signaling pathway. The latter has recently been shown to occur
in RCC cell lines [65]. To the best of our knowledge, structural defects in the TAP genes
are a rare event. Until now, mutations in TAP have been identified in two human tumor
cell lines, which are associated with the loss of constitutive and IFN-g-inducible
HLA class Iantigen expression due to instability of the empty HLA class I/b2-m complex
on the cell surface. In a lung carcinoma cell line a point mutation in exon 10 of
TAP1 introduces a premature stop codon, thereby resulting in a dysfunctional TAP1
protein [66] (Fig. 5.10B). Recently, Seliger et al. [162] have identified a base pair deletion
at position 1489 in the TAP1 subunit of a melanoma cell line; the resulting
frame-shift introduces an early stop codon. The dysfunctional TAP1 protein lacks
ATP-binding, peptide-binding and peptide-translocation properties, which could be
corrected by wild-type TAP1 gene transfer into these melanoma cells.
5.5.3
Selective Loss or Down-regulation
Fig. 5.11 Association of deficient TAP
expression with the metastatic phenotype.
A representative example of immunohistochemical
staining of a primary
and metastatic RCC lesion with an anti-
TAP1mAb is shown. TAP1expression is
strongly down-regulated in the metastasis
when compared to the primary tumor
lesion. (see color plates page XXII)
The most common type of MHC class Ialteration is represented by the selective loss
or down-regulation of MHC class Iallospecificities in malignant cells (Fig. 5.13).
Although antigenic peptides are generated and transported into the ER, the trimeric
complex cannot be formed and the peptides are not presented to CTLs. This type of