CD1D Gene Regulation in Cancer

Qiaoyi Chen, MD, PhD, Principal Investigator
Natalie Jackson

Abstract
CD1D molecules are involved in the presentation of lipid or glycolipid antigens that stimulate a subset of natural killer (NK) T cells which are involved in tumor cell rejection. A decreased number or an impaired function of NK T cells has been observed in patients with malignant tumor. This may explain why hematological malignant cells that express CD1d and can present effectively exogenous antigen to NK T cells can escape from NK T cells' antitumor surveillance. An effective strategy to boost the number or restore the function of NK T cells in patients with tumor would be very useful in antitumor immunity. The development of such a strategy relies on understanding the mechanism that results in impaired NK T cell regulation. Recent studies suggest that cross regulation between CD1d and NK T cells is required for NK T cell regulation. We hypothesize that a disturbance in the transcriptional or post-transcriptional regulation of the CD1D gene can affect such cross-regulation and result in impaired NK T cell function in antitumor surveillance. We found that the human CD1D gene has dual promoters and is associated with a CpG island. DNA hypermethylation in CpG islands has been associated with alteration of gene regulation in cancer. We also found that malignant tumor cells with CD1D promoter activity and CD1D mRNA do not necessarily express overt CD1d, suggesting that post-transcriptional CD1D gene regulation may play a role in the escape of tumor cells from NK T cells' surveillance. To understand CD1D gene regulation and its pathogenic association with the hematopoietic tumor cells, we propose to (1) define the cis-acting regulatory elements that control CD1d expression; (2) define the role of DNA methylation of the CD1D CpG island in association with CD1D gene regulation; and (3) define post-transcriptional CD1D regulation in hematopoietic tumor cells. The knowledge obtained from this application will help to elucidate the unique human CD1D regulatory mechanism and help to identify better strategies for restoring NK T cell regulation in patients with malignant tumor.

Sponsor: NIH
Duration: 01/04 - 12/09