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

5.6 MHC Class I Alterations: Impact on Immune Responses and Clinical Relevance
of TAAs remains to be analyzed in terms of the frequency of occurrence in vivo and
its effect on the natural history of the disease [77]. In addition, the role of the downregulation
of the MHC/peptide/epitope density for CTL-mediated recognition is controversially
discussed. It has been postulated that as few as one peptide/MHC complex
presented on a target is sufficient to elicit a potent CTL response [78]. However,
the naturally occurring variation in the expression of TAAs and/or MHC class Isurface
molecules modulates the sensitivity of target cells to CTL-mediated lysis demonstrating
a strictly quantitative relationship between MHC/antigen expression and
CTL response [79]. This gradualness of heterogeneity suggests a potential mechanism
for the progressive adjustment of tumor cells to a putative immunologically unfavorable
environment.
It is generally accepted that MHC class I-deficient cells are susceptible to lysis by NK
cells [80, 81] (see Fig. 5.5). The complementary interaction between loss of HLA class
Iexpression and gain in NK cell sensitivity has been shown to be associated with the
evolution of patients` immune responses over the course of several years demonstrating
an increased sensitivity to NK cell-mediated lysis [39]. The level of MHC
class Iexpression therefore influences the presentation and immunogenicity of CTL
epitopes and the modulation of NK cell response. Thus, therapeutic approaches leading
to the stimulation of the innate immunity in general and NK cell activity in particular
may be of specific clinical significance for the treatment of MHC class I ± tumors.
However, one has to consider that the loss of MHC class Imolecules usually
only occurs in a subset of the tumor due to its heterogeneity. A large fraction of tumor
cells can exhibit total loss while a subpopulation might express normal levels of
MHC class Iantigens on the cell surface. In functional terms, this tumor would still
be largely affected by the immune system.
The down-regulation of MHC class Isurface antigens on tumors is often associated
with the deficient expression of MHC class IAPM components, in particular of the
peptide transporter TAP. Animal experiments demonstrate that TAP over-expression
in tumor cells can improve their immunogenicity as well as the host survival [82].
This has been attributed to an enhanced presentation of antigenic peptides. Targeting
of TAP into tumor-burdened individuals may provide a possible method for antitumor
immune therapy by controlling the occurrence of metastasis. Furthermore,
TAP vaccines are independent of TAA expression and MHC polymorphism, both representing
major problems for the induction of T cell-mediated immune responses.
The functional significance of the selective MHC class Iallele loss has only been investigated
in a few cases, and has mainly been described in mutant cells generated
by mutagenesis and immune selection [83, 84]. Loss of a single HLA allele causes in
vitro resistance of tumor cells to lysis by TAA-specific CTLs using the lost allele as restricting
element [84, 85]. These allele-specific alterations of the MHC class IHC
might reflect tumor adaptation to immune selection attributable to a dominant immune
response restricted by a single MHC class Imolecule, thereby explaining its
high frequency [86]. The selection of HLA loss variants could severely affect the clinical
outcome of patients as well as the design of immunotherapies. A combination of
MHC class Iallelic loss with the expression of HLA-C molecules (Fig. 5.16) which interact
with the KIRs to maintain the inhibitory signal to NK cells is found in a minor-
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