HDAC5 controls the functions of Foxp3+ T‐regulatory and CD8+ T cells

• Published in: International journal of cancer Vol. 138; no. 10; pp. 2477 - 2486
• Main Authors: Xiao, Haiyan, Jiao, Jing, Wang, Liqing, O'Brien, Shaun, Newick, Kheng, Wang, Liang‐Chuan S., Falkensammer, Eva, Liu, Yujie, Han, Rongxiang, Kapoor, Veena, Hansen, Finn K., Kurz, Thomas, Hancock, Wayne W., Beier, Ulf H.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.05.2016
• Subjects: Adenocarcinoma; Animals; Cancer; cancer immunotherapy; Cancer therapies; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cytokines - biosynthesis; Forkhead Transcription Factors - metabolism; Foxp3; Foxp3 protein; Gene Deletion; Gene Targeting; HDAC; Histone deacetylase; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Immune response; Immune system; Immunoregulation; Interferon-gamma - biosynthesis; Isoforms; lung adenocarcinoma; Lung cancer; Lungs; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Medical research; Mice; Mice, Knockout; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; T cell receptors; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Treg; Tumor cells; Foxp3; Treg; cancer immunotherapy; lung adenocarcinoma; HDAC
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29979

Histone/protein deacetylases (HDACs) are frequently upregulated in human malignancies and have therefore become therapeutic targets in cancer therapy. However, inhibiting certain HDAC isoforms can have protolerogenic effects on the immune system, which could make it easier for tumor cells to evade the host immune system. Therefore, a better understanding of how each HDAC isoform affects immune biology is needed to develop targeted cancer therapy. Here, we studied the immune phenotype of HDAC5–/– mice on a C57BL/6 background. While HDAC5–/– mice replicate at expected Mendelian ratios and do not develop overt autoimmune disease, their T‐regulatory (Treg) cells show reduced suppressive function in vitro and in vivo. Likewise, CD4+ T‐cells lacking HDAC5 convert poorly to Tregs under appropriately polarizing conditions. To test if this attenuated Treg formation and suppressive function translated into improved anticancer immunity, we inoculated HDAC5–/– mice and littermate controls with a lung adenocarcinoma cell line. Cumulatively, lack of HDAC5 did not lead to better anticancer immunity. We found that CD8+ T cells missing HDAC5 had a reduced ability to produce the cytokine, IFN‐γ, in vitro and in vivo, which may offset the benefit of weakened Treg function and formation. Taken together, targeting HDAC5 weakens suppressive function and de‐novo induction of Tregs, but also reduces the ability of CD8+ T cells to produce IFN‐γ. What's new? Many cancers bump up their production of histone deacetylases, HDACs, but treatment designed to rein them in can impede the immune system's own efforts against the tumor. These authors investigated the immune function of mice that lack HDAC5. They expected that eliminating HDAC5, like other HDACs, would boost regulatory T cells (Tregs), which suppress other T cells from proliferating and curb immune attacks. Quite the opposite, mice lacking HDAC showed weakened Treg function. Although this did not translate to improved anti‐cancer immunity—possibly because of decreased interferon production—this new observation could lead to more specific anti‐HDAC treatments.