Changes in Immunogenicity of Chronic Lymphocytic Leukemia Cells Mediated by Epigenetic Modifiers

The success of immunotherapeutic treatments for B-cell chronic lymphocytic leukemia (B-CLL) hinges upon the circumvention of tolerogenic mechanisms which inhibit the formation of a robust anti-cancer immune response. Recent evidence suggests that DNA methylation inhibitors and histone deacetylase inhibitors can have lasting cancer-specific effects on the expression of highly immunogenic cancer-testis antigens (CTAs) as well as modulating costimulatory and major histocompatability molecule (MHC) surface expression. To investigate the potential efficacy of a combined therapy of methylation (5-aza-2′ytidine) and histone deacetylase (LAQ) inhibitors in human B-CLL we evaluated the expression of CTAs, costimulatory molecules (CD40, CD80, CD86), and MHC molecules (HLA-A, B, C, and HLA-DR) in both cell lines and primary cells from patients with CLL. In addition, we investigated the overall functional immunogenicity of treated B-CLL cells using mixed leukocyte reactions. Results showed that many highly immunogenic CLL-specific CTAs (SSX family, MAGE family, NY-ESO-1, GAGE-2, and NXF2) are significantly upregulated after treatment with both inhibitors. Our data also indicates that the combined effect of both inhibitors was capable of inducing a more immunogenic phenotype (increased CD86, CD80, CD40, HLA-A,B,C, and HLA-DR) in CLL cells consistently, while either drug alone was incapable of producing this effect. In addition treatment with both inhibitors was capable of increasing IFNγ release mediated by allogenic T-cells. Taken together these data indicate that a combined therapy with histone deacetylase and methylation inhibitors, possibly in combination with antigen-specific vaccine immunotherapy, may effectively induce cancer-specific antigen expression and increase costimulatory and antigen presenting capacity of the B-CLL cell.