Tumor formation in immunocompetent hosts is believed to be dependent on the ability of
tumor cells to evade the immune system, as suggested by the alterations of expression of the major histocompatibility complex (MHC) and related molecules in a number of
cancers. Our previous serial analysis of gene expression (SAGE) study revealed that
HLA-DRA (encoding the alpha chain of
HLA-DR) is one of the most highly overexpressed genes in
ovarian cancer. This finding was unanticipated, as overexpression of MHC molecules would be expected to increase
tumor immunogenicity, therefore compromising
tumor growth. We have now examined the expression of
HLA-DR alpha chain in ovarian and a variety of other
cancers using tissue arrays and found it overexpressed in a majority of the
cancer tissues investigated. In contrast, the
HLA-DR beta chain, which together with the alpha chain forms the functional
HLA-DR complex, was not frequently found expressed in
cancer, resulting to a lack of mature
HLA-DR in these tissues. Interestingly, HLADRA and HLADRB transcripts were both found expressed in many other
cancer types, including
ovarian cancer, suggesting that the downregulation of HLADR beta chain is a post-transcriptional or post-translational mechanism. In addition, we observed high levels of the
invariant chain (Ii/CD74) expression in both the cytoplasm and plasma membrane of ovarian
tumor cells, possibly contributing to the lack of mature
HLA-DR protein expression. Interestingly, we found that IFN-gamma could induce mature
HLA-DR at the surface of normal ovarian cells, while this ability was reduced in
tumor cells. Together, these data suggest that, while ovarian
tumors overexpress
HLA-DR alpha, perhaps as a result of inflammatory events in the tumor microenvironment, the
tumor cells may have compensatory mechanisms to reduce the production of functional
MHC class II molecules, thus reducing immunogenicity and favoring
tumor growth. In addition, because of its ubiquitous expression in ovarian and other
cancers,
HLA-DR alpha may represent a novel
biomarker for
malignancy.