Targeting Histone Deacetylase 6 (HDAC6) as a Novel Approach to Overcome T-Cell Anergy
| Autor: | Eduardo M. Sotomayor, Zi Wang, Jennifer Rock-Klotz, Ajay Gill, Danay Marante, Fengdong Cheng, Alejandro Villagra, Javier Pinilla-Ibarz, Karrune Woan, Oscar Merino, Hongwei Wang, Edward Seto, Lianet Vazquez |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | Blood. 116:1483-1483 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v116.21.1483.1483 |
| Popis: | Abstract 1483 The anti-inflammatory molecules IL-10 and STAT3 are major hurdles in our efforts to harness effective anti-tumor immunity1. Previously, we have unveiled a role for histone deacetylase 11 (HDAC11) as a negative regulator of IL-10 gene transcriptional activity in antigen-presenting cells (APCs)2. In an effort to better characterize the epigenetic influences upon IL-10, we screened other HDACs and found that over-expression of HDAC6 in the macrophage cell line RAW264.7 was able to transcriptionally upregulate IL-10 in response to LPS. Next, using lentiviral vectors encoding shRNA for HDAC6, we generated stable knockdown clones of HDAC6 (HDAC6KD). In contrast to HDAC6 overexpression, HDAC6KD cells produced less IL-10 both at the mRNA and protein levels. Further analysis of HDAC6KD clones revealed elevated expression of the co-stimulatory molecule B7.2. Functionally, LPS-stimulated HDAC6KD cells were better able to activate anti-HA (hemagglutinin-influenza) transgenic CD4+ T cells to produce IL-2 and IFN-γ. More relevant to the tumor setting, anti-HA CD4+ anergic T cells isolated from animals bearing HA-expressing A20 B-cell lymphoma regained their ability to produce IL-2 and IFN-γ when cultured in vitro with HDAC6KD cells in the presence of cognate HA-antigen. These same T-cells remained anergic when cultured with control APCs displaying normal levels of HDAC6. Mechanistically, we have found that APCs lacking HDAC6 display a significant abrogation of STAT3 activation in response to LPS stimulation. Given the demonstration that HDACs, other than HDAC6, can regulate STAT3 activity3, we are actively investigating whether the effect we have observed is a result of direct HDAC6-STAT3 interaction or a diminished autocrine signaling through IL-10. Taken together, through abrogation of two well-known tolerogenic mechanisms in APCs, IL-10 and STAT3, HDAC6 inhibition represents an attractive therapeutic approach to overcome tumor-induced T-cell anergy and tip the balance towards effective anti-lymphoma immunity. 1. Cheng F., et al. Immunity 2003 Sep;19(3):425-36. 2. Villagra A., et al. Nat Immunol. 2009 Jan;10(1):92-100. 3. Yuan Z., et al. Science. 2005 Jan 14;307(5707):269-73. Disclosures: No relevant conflicts of interest to declare. |
| Databáze: | OpenAIRE |
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