Restoring the functional immunogenicity of chronic lymphocytic leukemia using epigenetic modifiers

Abstract

Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endowed with intrinsic antigen-presenting capabilities. Such a function however is lost during malignant transformation and CLL cells are well known for their inability to process and present antigens to the T-cell arm of the immune system. Instead, malignant CLL cells elicit a vast array of immune regulatory mechanisms conducive to T-cell dysfunction and immunosupression. Previously, we have shown that treatment of CLL cells with the demethylating agent 5-aza-2′-deoxycytidine unleashed target antigen expression. Here we show for the first time that combining two epigenetic modifiers, 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor LAQ824 effectively restores the immunogenicity of CLL cell lines as well as primary cells obtained from CLL patients. Indeed, such a combination induces the expression of novel and highly antigenic cancer testis antigens (CTAs) and co-stimulatory molecules. These changes facilitate the formation of robust supramolecular activation complexes (SMAC) between CLL cells and responder T-cells leading to intracellular signaling, lytic granule mobilization, and polarization of functional and relevant T-cell responses. This cascade of T-cell activating events triggered by CLL cells with restored APC function, points to combined epigenetic modifier treatment as a potential immunotherapeutic strategy for CLL patients.

Epigenetic repolarization of T lymphocytes from chronic lymphocytic leukemia patients using 5-aza-2′-deoxycytidine

“…A single manuscript has previously identified the epigenetic repolarization of human tumor infiltrating lymphocyte clones using 5A2, however the scope of this study lacked a detailed analysis of the mechanism and molecular phenotype [23]. In prior published studies we identified a number of demethylation-induced immunotherapeutic effects which in total lead to an increased antigen presenting phenotype in CLL cells, a result which complements our current findings [27]. …”

Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia

“…Our group has also reported findings establishing a role for epigenetic modifiers in altering CLL biology. 7,8 Interestingly, various groups have reported elevated histone deacetylase (HDAC) expression in CLL B cells compared with HDAC expression in normal B cells and correlations of HDAC expression levels with prognostic factors. [9][10][11][12] Several studies have also begun to explore the therapeutic potential of HDAC inhibitors for CLL treatment.…”

Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

“…39 In a later study, the epigenetic modifiers 5-aza-2-deoxycytidine and LAQ824 effectively restored immunogenicity in CLL cell lines and primary CLL patient cells. 40 The combination treatment simultaneously improved T-cell activation and APC function of CLL B cells.…”