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

5.7 The Role of MHC Class II Processing and Presentation in Tumors 81
5.7.2
Molecular Mechanisms of Deficiencies in the MHC class II APM
Qualitative differences in the MHC class II antigen-processing and -presentation
pathway may be instrumental in shaping the CD4 + T cell response directed against
tumor cells (Fig. 5.18). Although multiple components of this pathway have been
identified, their expression has not been analyzed systematically in human malignancies.
Therefore, only limited information exists about defects in the MHC class
II APM in human tumors especially concerning their functional significance. It is
assumed that the timing and location of the MHC class II antigen expression is carefully
controlled since aberrant expression of these molecules may lead to immune
escape mechanisms of the tumor [108].
The transcription of the genes encoding the three MHC class II isotypes HLA-DR,
-DP and -DQ is coordinately regulated by a set of conserved cis-acting promoter elements.
One key regulator is the MHC class II transactivator CIITA, a non-DNA binding
protein. CIITA expression is directly correlated with MHC class II surface expression
and can be induced by IFN-g. Thus, CIITA expression functions as a molecular
switch for MHC class II gene regulation and is physiologically controlled during the
cell cycle [109]. The lack of constitutive and/or IFN-g-mediated CIITA expression has
been detected in a number of tumor cells and may be attributable to dysregulation or
structural alterations of CIITA. Defects in the allele locus which encodes the CIITA
factor therefore result in deficient MHC class II surface expression. This mechanism
has been shown in plasmocytoma, small cell lung carcinoma and hepatocarcinoma
cells in which MHC class II antigen expression can be corrected by CIITA transfection
[110±112]. In addition, defective CIITA expression is associated with lack of inducibility
of class II antigen expression in many tumors and may at least partially be associated
with the heterogeneity of MHC class II expression in tumors [111]. Furthermore,
induction of MHC class II antigens requires retinoblastoma tumor suppressor
gene [111]. Nitric oxide (NO) strongly inhibits the IFN-g-stimulated expression of
CIITA. This causes deficient expression of the family of genes regulated by CIITA,
such as the Ii, HLA-DM and MHC class II molecules [113], suggesting that NO is an
inhibitor of immune responses during malignant transformation by decreasing antigen
presentation and subsequently CD4 + T cell activation. The CIITA-mediated regulation
of MHC class Isurface expression is controversially discussed. In this case,
CIITA controls the expression of the MHC class I HC and b2-m, whereas the expression
of components of the MHC class IAPM, such as the peptide transporter TAP, are
not affected [114]. Together, this transcription factor plays a crucial role in the design
of both the MHC class Iand IIantigen-mediated immunotherapeutic approaches.
5.7.3
Modulation of Immune Response by Altered MHC Class II Expression
Alterations in the peptide repertoire presented by MHC class II molecules on tumor
cells affect the generation of CD4 + T cell response. Although HRS cells express all
key effector molecules of APC, they fail to evoke an effective immune response. This