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

5.7 The Role of MHC Class II Processing and Presentation in Tumors
result in increases of MHC class Isurface expression in regions distant from the inflammatory
site.
However, some tumors are resistant to IFN-g treatment. This can be due either to
mutations in the IFN-g receptor (R) or to deficiencies in components of the IFN-g
signal transduction pathway, e. g. the IFN-regulatory factors (IRFs [91, 92]; for
further information, see Chapter 8). In addition to the IFNs, TNF-a has also been
shown to affect the MHC class Iantigen processing and presentation by coordinately
modulating the expression of components of the MHC class Ipathway. Thus, TNF-a
may be useful when a concerted up-regulation of the MHC class IAPM is required,
but cannot be achieved by IFN-g [93].
5.7
The Role of MHC Class II Processing and Presentation in Tumors
The normal expression pattern of MHC class II genes is restricted to professional
APCs, thymic epithelium and B cells. MHC class II induction can occur on most cell
types through the exposure to various cytokines, in particular to IFN-g [3]. The expression
of MHC class II antigens on cells other than APCs can aid in the initiation
and maintenance of an acute immune response.
Most human tumors do not express MHC class II molecules and the direct presentation
pathway for activation of CD4 + T cells is therefore not available. In general,
CD4 + T cell activation for these tumors depends exclusively on the indirect presentation
via professional APCs. Limited CD4 + T cell responses to such tumors may reflect
the inefficiency of cross-priming. Immunization experiments using MHC class
II-expressing tumor cells demonstrated that tumor cells are the predominant APCs
in vivo for priming naÒve CD4 + T cells. Thus, their inclusion into cancer vaccines
may enhance activation of tumor-reactive CD4 + T cells [94].
5.7.1
Frequency and Clinical Impact of MHC Class II Expression on Tumors
There is considerable evidence that the aberrant expression of MHC class II antigens
and of the components involved in MHC class II antigen processing has pathophysiological
consequences in malignant diseases. The constitutive or regulated expression
of these proteins in tumors influences their immunity. The frequency of constitutive
and/or IFN-g-induced MHC class II expression varies between the different
tumor types analyzed, but is usually associated with the co-expression of Ii and HLA-
DM. One could distinguish three MHC class II phenotypes in human tumors: noninducible,
inducible and constitutive [95] (Fig. 5.17). It is generally assumed that the
IFN-g-inducible phenotype is normal, whereas the non-induced and constitutive
MHC class II phenotypes are a result of neoplastic transformation.
The non-inducible MHC class II phenotype may represent a mutant cell line missing
the required factors involved in the IFN-g-mediated induction. Thus, it is questioned
whether the tumor habors a mutation that prevents MHC class II inducibility,
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