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De novo Induction of a Cancer/Testis Antigen by 5-Aza-2'-Deoxycytidine Augments Adoptive Immunotherapy in a Murine Tumor Model

¹ Thoracic Oncology Section and ² Tumor Immunology Section, Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland; ³ Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, Ohio; and ⁴ University of Pittsburgh Cancer Institute and Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: Z. Sheng Guo, University of Pittsburgh Cancer Institute, UPCI Research Pavilion, 1.46, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-7711; Fax: 412-623-7709; E-mail: guozs{at}upmc.edu.

Recent studies suggest that immunotherapy targeting specific tumor-associated antigens (TAAs) may be beneficial in cancer patients. However, most of these TAAs are tumor type specific and heterogeneous among patients, thus limiting their applications. Here, we describe the de novo induction of a cancer/testis antigen (CTA) for immunotherapy of tumors of various histologies. The murine CTA P1A, normally expressed only in a few tumor lines, could be induced de novo in all P1A-negative cancer lines of eight histologic origins in vitro and in various murine xenografts by systemic administration of 5-aza-2'-deoxycytidine. The induction of P1A expression correlated strongly with demethylation of the CpG island in the promoter region of this gene. The induced antigen was processed and presented properly for recognition by H-2L^d-restricted P1A-specific CTLs. The combination of a demethylating agent and adoptive transfer of P1A-specific CTL effectively treated lung metastases in syngeneic mice challenged with P1A-negative 4T1 mammary carcinoma cells. These data show a novel strategy of combined chemoimmunotherapy of cancer targeting a CTA induced de novo in a broad range of tumor histologies, and support further evaluation of chromatin-remodeling agents for human cancer therapy. (Cancer Res 2006; 66(2): 1105-13)

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