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

Abstract

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-2V -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 drestricted 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)

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models

“…30,31 The integrity of RNA and random primers-synthesized cDNA was confirmed by the amplification of all cDNA samples with mouse b-actin-specific primers, as previously described. 6 Five mL of each RT-PCR sample were run on Quantitative Methylation-Specific PCR analyses Bisulfite conversion was carried out on 500 ng genomic DNA using EZ DNA Methylation-Gold TM Kit (Zymo Research, cat # D5005), according to the manufacturer's protocol.…”

Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b

“…The medical importance of CG-X antigens is supported by the observation that vaccine-induced CD8 þ T-cell responses to CG-X antigens, but not to melanoma differentiation antigens, correlates with tumor-free and overall survival in melanoma patients (Reynolds et al, 2003). Treatment with agents that increase the expression of CG-X antigens, including DAC (Karpf et al, 2004;Sigalotti et al, 2004) and zebularine (Cheng et al, 2004), constitute an intriguing therapeutic approach by which antitumor immunity to CG-X antigen-directed vaccines could be improved (Karpf and Jones, 2002;Maio et al, 2003;Guo et al, 2006). However, the toxicity and pleiotropic effects associated with nucleoside analog DNMT inhibitors could be a barrier to the successful clinical implementation of this combination strategy (Karpf and Jones, 2002).…”

Azacytidine treatment after discontinuation of immunosuppressants in patients with myelodysplastic syndrome and relapse after allo-SCT at a single center

“…4 With regard to transplantation, recent studies have suggested that hypomethylating agents may potentiate GVL effects. [5][6][7][8] Therefore, a pilot study of azacytidine treatment after discontinuation of immunosuppressants was performed in MDS patients who relapsed after transplantation.…”