Restoring the functional immunogenicity of chronic lymphocytic leukemia using epigenetic modifiers.
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.
Dubovsky
Jason A
JA
Department of Malignant Hematology, Immunology, and Experimental Therapeutics, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
Wang
Daniel
D
Powers
John J
JJ
Berchmans
Emmanuel
E
Smith
Matthew A
MA
Wright
Kenneth L
KL
Sotomayor
Eduardo M
EM
Pinilla-Ibarz
Javier A
JA
D000107:Acetylation / Q000187:drug effects; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D004357:Drug Synergism; D057890:Epigenomics; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D016130:Immunophenotyping; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D008297:Male; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D006657:Histones; D006877:Hydroxamic Acids; C477361:LAQ824; D000077209:Decitabine; D007770:L-Lactate Dehydrogenase; D001374:Azacitidine