Anomalous expression of the HLA-DR α and β chains in ovarian and other cancers

Leticia B A Rangel, Rachana Agarwal, Cheryl A. Sherman-Baust, Valeria De Mello-Coelho, Ellen S. Pizer, Hongxiu Ji, Dennis D. Taub, Patrice J. Morin

Research output: Contribution to journalArticlepeer-review

Abstract

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 α 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 α 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 β chain, which together with the α 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 β 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-γ 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 α, 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 α may represent a novel biomarker for malignancy.

Original languageEnglish (US)
Pages (from-to)1021-1027
Number of pages7
JournalCancer Biology and Therapy
Volume3
Issue number10
StatePublished - Oct 2004
Externally publishedYes

Keywords

  • Biomarker
  • CD74
  • Class II MHC
  • HLA-DR
  • Ii
  • Immunoediting
  • Ovarian cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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