title: Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function.
abstract: Myeloid-derived suppressor cells (MDSCs), 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.
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States; Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Eva
authors.initials: E
authors.lastname: Sahakian
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Powers
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Deng
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Fengdong
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Distler
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: David M
authors.initials: DM
authors.lastname: Woods
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rock-Klotz
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Andressa L
authors.initials: AL
authors.lastname: Sodre
authors.affiliation: The Wistar Institute, Philadelphia, PA, United States.
authors.forename: Je-In
authors.initials: JI
authors.lastname: Youn
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Karrune V
authors.initials: KV
authors.lastname: Woan
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Villagra
authors.affiliation: The Wistar Institute, Philadelphia, PA, United States.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Gabrilovich
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States; Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Sotomayor
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States; Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States. Electronic address: javier.pinilla@moffitt.org.
authors.forename: Javier
authors.initials: J
authors.lastname: Pinilla-Ibarz
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002451:Cell Compartmentation; D002454:Cell Differentiation; D049109:Cell Proliferation; D002469:Cell Separation; D044127:Epigenesis, Genetic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology*
chemical_list: D039481:CD11b Antigen; C485184:enhanced green fluorescent protein; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; C528111:Hdac11 protein, mouse; D006655:Histone Deacetylases
keywords: HDAC11; Immuno-suppression; MDSCs; Myelopoiesis