Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function
| Autor: | Jie Chen, David M. Woods, Eva Sahakian, Eduardo M. Sotomayor, John Powers, Jennifer Rock-Klotz, Fengdong Cheng, Alejandro Villagra, Karrune Woan, Je In Youn, Dmitry I. Gabrilovich, Allison Distler, Susan L. Deng, Andressa L. Sodre, Javier Pinilla-Ibarz |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Myeloid
Cellular differentiation T cell Immunology Population Green Fluorescent Proteins Regulator Mice Transgenic Cell Separation Biology Histone Deacetylases Article Epigenesis Genetic medicine Animals Myeloid Cells education Molecular Biology Cell Proliferation Tumor microenvironment education.field_of_study CD11b Antigen HDAC11 Cell Differentiation Cell biology Cell Compartmentation Interleukin-10 Mice Inbred C57BL medicine.anatomical_structure Myeloid-derived Suppressor Cell |
| Zdroj: | Molecular immunology. 63(2) |
| ISSN: | 1872-9142 |
| Popis: | Myeloid-derived suppressor cells (MDSC's), a heterogeneous population of cells capable of suppressing anti-tumor T cell function in the tumor microenvironment, represent an imposing obstacle in the development of cancer immunotherapeutics. Thus, identifying elements essential to the development and perpetuation of these cells will undoubtedly improve our ability to circumvent their suppressive impact. HDAC11 has emerged as a key regulator of IL-10 gene expression in myeloid cells, suggesting that this may represent an important targetable axis through which to dampen MDSC formation. Using a murine transgenic reporter model system where eGFP expression is controlled by the HDAC11 promoter (Tg-HDAC11-eGFP), we provide evidence that HDAC11 appears to function as a negative regulator of MDSC expansion/function in vivo. MDSCs isolated from EL4 tumor-bearing Tg-HDAC11-eGFP display high expression of eGFP, indicative of HDAC11 transcriptional activation at steady state. In striking contrast, immature myeloid cells in tumor-bearing mice display a diminished eGFP expression, implying that the transition of IMC to MDSC's require a decrease in the expression of HDAC11, where we postulate that it acts as a gate-keeper of myeloid differentiation. Indeed, tumor-bearing HDAC11-knockout mice (HDAC11-KO) demonstrate a more suppressive MDSC population as compared to wild-type (WT) tumor-bearing control. Notably, the HDAC11-KO tumor-bearing mice exhibit enhanced tumor growth kinetics when compare to the WT control mice. Thus, through a better understanding of this previously unknown role of HDAC11 in MDSC expansion and function, rational development of targeted epigenetic modifiers may allow us to thwart a powerful barrier to efficacious immunotherapies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect