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

expressing tumor cells, which is consistent with the idea that endogenous TAAs are
presented by exogenously expressed MHC class II molecules and that the Ii chain
blocks the loading of the tumor antigen [97]. Furthermore, CIITA-transfected tumor
cells are less efficient in generating antitumor immunity which could be mediated
by the CIITA-facilitated activation of Ii expression. These results support the idea
that tumor cell expression of MHC class II antigens under specific circumstances
could lead to an antitumor immunity. However, these animal models raise the question
about the differences in the development of human tumors. In the latter, IFN-g
can induce the Ii as well as CIITA. Mach et al. [116] demonstrated that antigen presentation
requires both CIITA and IFN-g treatment. Whether this is true for other
cases may depend on the antigen required for MHC class II-dependent responses
and the allele mediating the response. However, the identification of additional roles
of MHC class II expression in the tumor development will depend on the characterization
of a large series of MHC class II-presented TAAs or MHC class II-binding
peptides as well as on the development of in vitro assays for TAA presentation to
CD4 + T cells.
These results suggest that there exist a number of possible tumor cell defects that
could account for the lack of tumor cell immunogenicity regarding HLA class II expression.
These include the lack of certain MHC class II alleles to bind antigenic
peptide in specific tumor types. If MHC class II expression can mediate tumor immunogenicity
and MHC class II antigens are inducible or constitutively expressed in
tumor cells, one can postulate that the impaired antitumor response is caused by deficiencies
distinct from that of MHC class II antigen-processing and -presentation
molecules. The molecular basis of constitutive expression of MHC class II in solid
tumors is still unknown, but it likely involves the activation of CIITA which could be
due to partial or total activation of the IFN-g signaling pathway in these cells thereby
resulting in the activation of CIITA.
5.8
Role of IFN-c in Immunosurveillance
5.8 Role of IFN-g in Immunosurveillance 83
IFN-g is a pleiotropic cytokine which plays a central role in promoting immune responses
directed against virus-infected or malignant transformed cells. It exerts its
biological activities by interacting with the IFN-gR that is ubiquitiously expressed on
most cell types. This directly leads to an activation of the janus tyrosine kinase
(JAK)/signal transducers and activation of transcription (STAT) pathway [117].
STAT1 can be also activated by IFN-a and sodium butyrate [118]. The IRFs mediate
the downstream effects of STAT1 activation. They belong to a large family of transcription
factors. These molecules are important for the regulation of cell growth
and transformation upon IFN treatment. IRF1 and IRF2 represent the best characterized
family members and exert their biological activity by binding to the IRF element
(IRF-E) which has been identified in the promoter of many IFN-inducible
genes, including the MHC class Iand IIantigens, TAP1 and LMP2 as well as the
transactivator CIITA [92, 121±123] (Fig. 5.19). IRF2 is the major activator of the IFN-