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

Abstract

T cell immune dysfunction has an important role in the profound immunosupression that characterizes chronic lymphocytic leukemia (CLL). Improper polarization of T cells has been proposed as one of the mechanism involved. Mounting data implicates chromatin regulation, namely promoter methylation, in the plasticity of naïve human T cells. Recent in vitro evidence indicates that this plasticity may be phenotypically altered by using methylation inhibitors which are approved for clinical use in certain types of cancer. These results beg the question: can the ineffective polarization of T lymphocytes in the context of CLL be effectively modulated using methylation inhibitors in a sustainable therapeutic fashion? To answer this question our laboratory has studied the effects of 5-aza-2′-deoxycytidine (5A2) in helper and cytotoxic T lymphocytes from healthy donors and CLL patients in well characterized molecular and epigenetic signaling pathways involved in effective polarization. Moreover, we sought to investigate the consequences of methylation inhibitor treatment on lymphocyte survival, activation intensity, and naïve cell polarization. Our data indicates that 5A2 treatment can repolarize Th2 cells to effectively secrete interferon gamma, signal via T-bet, and achieve demethylation of critical Th1 specific promoters. Moreover, we demonstrate that 5A2 can force Th1 polarization of naïve T cells despite a strong IL-4 stimuli and a lack of IL-12. In conclusion our data seeks to define a modality in which improper or ineffective T cell polarization can be altered by 5AZA and could be incorporated in future therapeutic interventions.

Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome

“…However, Schmiedel found that although initially impaired, IFN-γ production was recovered and even increased as compared to controls when NK cells were treated for 4 days with 5-aza under IL-2 stimulation [ 33 ] thereby supporting our results that proliferating cells with active incorporation of 5-aza acquire a heightened functionality. A recent study also demonstrated that decitabine treatment can depolarize Th2 cells to effectively secrete IFN-γ, signal via T-bet, and achieve demethylation of critical Th1 specific promoters [ 49 ]. The net effect of 5-aza on NK cell anti-tumor responses was recently investigated in B cell precursor acute lymphoblastic leukemia (BCP-ALL) bearing humanized mice.…”

Boswellic acid attenuates asthma phenotype by downregulation of GATA3 via nhibition of PSTAT6

“…It was found that not only can boswellic acid be used to treat asthma but also exert antitumor effects. Furthermore, it was effective in treating rheumatism, rheumatoid arthritis, colitis, and inflammatory reactions (Yao et al, 2011;Dubovsky et al, 2011;Souza et al, 2012;Li et al, 2013;Menet et al, 2013;Chakilam et al, 2013). Due to the relationship between asthma and inflammation, we found it valuable to investigate the expression of transcription factors associated with the inflammatory reaction to clarify the mechanism of action of boswellic acid.…”

Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model

“…While the presumed mechanism of action of these compounds was a direct antitumor effect, they can simultaneously modify antitumor immunity. Thus, they may not only act at the level of tumor cells, by modulating antigen expression and the machinery responsible for their presentation and recognition by T-cells [16,17], but they may also directly act on the immune system, activating effector cells [18,19] and inhibiting immunosuppressive mechanisms [20,21]. Accordingly, some of these compounds increase the efficacy of checkpoint inhibiting antibodies in different murine tumor models [22,23].…”