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

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5 Major Histocompatibility Complex Modulation and Loss
Fig. 5.19 Model of the regulation of MHC class II genes by
IFN-g. The constitutive expression of CIITA is mediated by a proximal
5' flanking sequence of the CIITA promoter III. In contrast,
the induction of this promoter by IFN-g is mediated by distal upstream
sequences. Binding of IFN-g to its receptor activates the
JAK kinases which subsequently results in the phosphorylation of
STAT1. STAT1 activation is accompanied by the activation of the
CIITA promoter directly via STAT1binding to sequences in this
region. In addition, STAT1activation induces the transcription of
the CIITA promoter IV both by binding directly to sequences in
this promoter or by inducing the transcription of IRF1which is
also required for the promoter activation. CIITA then activates the
transcription of MHC class II antigens, the Ii and HLA-DM genes
through common sequences located in the promoter regions of
these genes. (see color plates page XXIV)
g-inducible CIITA promoter type IV [123], but cooperates with IRF1 for the complete
activation of CIITA [123]. This promoter is used by many cell types, including fibroblasts
and endothelial cells [124].
5.8.1
IFN-c-dependent Immunosurveillance of Tumor Growth
The disruption of any step of IFN-g signaling may result in an abrogation of the host
antitumor response. Recently, the involvement of IFN-g in tumor immunosurveillance
has been studied in STAT1 as well as IFN-gR knockout mice using genetic or
carcinogen-dependent tumorigenesis model systems [119, 120]. It has been demonstrated
that the lack of IFN-g sensitivity predisposes a murine host to enhance tumor
development which leads to progressive tumor growth. These data suggest that IFN-g