Submitted May 24, 2008
Accepted November 20, 2008
Hypomethylating drugs convert HA-1 negative solid tumors
into targets for stem cell based immunotherapy
Lothar Hambach*, Kam-Wing Ling, Jos Pool, Zohara Aghai, Els Blokland, Hans J. Tanke, Jan A. Bruijn, Hans Halfwerk, Hester van Boven, Brigitte Wieles, and Els Goulmy
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
* Corresponding author; email: l.w.h.hambach{at}lumc.nl.
Clinical responses of solid tumors after allogeneic human leukocyte antigen-matched stem cell transplantation (SCT) often coincide with severe graft-versus-host disease (GvHD). Targeting minor histocompatibility antigens (mHags) with hematopoiesis- and cancer-restricted expression, e.g. HA-1, may allow boosting the anti-tumor effect of allogeneic SCT without risking severe GvHD. The mHag HA-1 is aberrantly expressed in cancers of most entities. However, estimated 30-40% of solid tumors do not express HA-1 (i.e. "HA-1neg") and cannot be targeted by HA-1 specific immunotherapy. Here, we investigated the transcriptional regulation of HA-1 gene expression in cancer. We found that DNA hypermethylation in the HA-1 promoter region is closely associated with the absence of HA-1 gene expression in solid tumor cell lines. Moreover, we detected HA-1 promoter hypermethylation in primary cancers. The hypomethylating agent 5-aza-2'-deoxycytidine induced HA-1 expression only in HA-1neg tumor cells and sensitized them for recognition by HA-1 specific cytotoxic T-lymphocytes. Contrariwise, the histone deacetylation inhibitor Trichostatin A induced HA-1 expression both in some HA-1neg tumor cell lines and in normal non-hematopoietic cells. Our data suggest that promoter hypermethylation contributes to the HA-1 gene regulation in tumors. Hypomethylating drugs might extend the safe applicability of HA-1 as immunotherapeutic target on solid tumors after allogeneic SCT.
