Restoring the functional immunogenicity of chronic lymphocytic leukemia using epigenetic modifiers

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Blank Restoring the functional immunogenicity of chronic lymphocytic leukemia

using epigenetic modifiers.

JA Dubovsky, D Wang, JJ Powers, E Berchmans, MA , KL , EM Sotomayor,

and JA Pinilla-Ibarz

Leuk Res, September 20, 2010; .

Department of Malignant Hematology, Immunology, and Experimental Therapeutics,

H. Lee Moffitt Cancer Center, Tampa, FL, USA.

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 immunosuppression.

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 costimulatory 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.

PMID: 20863567