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

80 5 Major Histocompatibility Complex Modulation and Loss
Fig. 5.17 Possible pathway for the generation
of an antitumor response dependent on the
MHC class II expression of tumor cells (according
to Blanck [95]). (I) The pathway which is directly
affected by a tumor cell mutation leading
to the generation of an antigenic, tumor-associated
peptide. (II) The pathway which is directly
affected by a tumor cell mutation due to inhibition
of the Th1response or secretion of immunosuppressive
cytokines. These mutations include
defects in the retinoblastoma gene preventing
MHC class II activation in response to IFN-g.
(III) The non-inducible expression could be
caused by deficiencies in the IFN-g signed transduction
pathway. (see color plates page XXIII)
such as IRF1, or alternatively, whether the MHC class II inducibility could be inhibited
by autocrine secretion of IL-10 or transforming growth factor (TGF)-b of the tumor
cells [95]. The molecular basis of the constitutive MHC class II surface expression
of tumor cells is unknown, but likely involves the inadequate activation of
CIITA. High levels of constitutive MHC class II antigen expression were demonstrated
in approximately 60% of nasopharyngeal tumors [96] and in a subset of malignant
cells of Hodgkin's disease, termed Reed±Sternberg (HRS [97]).
The clinical impact of MHC class II antigen expression by malignant cells varies
among tumors. Interestingly, there appears to exist an association between distinct
MHC class II alleles and the development of some cancers, e. g. gastric carcinoma
[98]. For some tumors, MHC class II antigen expression is associated with more aggressive
malignancies and poor prognosis, e.g. in melanoma and osteosarcoma [99±
101], whereas in others, such as squamous cell carcinoma, breast carcinoma, colorectal
carcinoma, cervical carcinoma and laryngeal carcinoma, MHC class II expression
directly correlates with a positive prognosis [102±106]. In breast carcinoma, MHC
class II expression is further associated with the degree of differentiation. In addition,
in melanoma, MHC class II antigens are not expressed in nevic cells, but can
be induced by ras-mediated transformation of melanocytes and are frequently expressed
by malignant cells [107].