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 Blood, 19 March 2009, Vol. 113, No. 12, pp. 2715-2722.
Prepublished online as a Blood First Edition Paper on December 18, 2008; DOI 10.1182/blood-2008-05-158956.

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IMMUNOBIOLOGY

Hypomethylating drugs convert HA-1–negative solid tumors into targets for stem cell–based immunotherapy

Lothar Hambach1, Kam-Wing Ling1, Jos Pool1, Zohara Aghai1, Els Blokland1, Hans J. Tanke2, Jan A. Bruijn3, Hans Halfwerk4, Hester van Boven4, Brigitte Wieles1, and Els Goulmy1

Departments of 1 Immunohematology and Blood Transfusion, 2 Molecular Cell Biology, and 3 Pathology, Leiden University Medical Center, Leiden; and 4 Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands

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, for example, HA-1, may allow boosting the antitumor effect of allogeneic SCT without risking severe GVHD. The mHag HA-1 is aberrantly expressed in cancers of most entities. However, an estimated 30% to 40% of solid tumors do not express HA-1 (ie, are 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. Contrarily, the histone deacetylation inhibitor trichostatin A induced HA-1 expression both in some HA-1neg tumor cell lines and in normal nonhematopoietic 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 an immunotherapeutic target on solid tumors after allogeneic SCT.


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