HDAC9 deficiency promotes tumor progression by decreasing the CD8⁺ dendritic cell infiltration of the tumor microenvironment.

BACKGROUND:The tumor microenvironment (TME) contains a variety of immune cells, which play critical roles during the multistep development of tumors. Histone deacetylase 9 (HDAC9) has been reported to have either proinflammatory or anti-inflammatory effects, depending on the immune environment. In this study, we investigated whether HDAC9 in the tumor stroma regulated inflammation and antitumor immunity. METHODS:Hdac9 knockout mice were generated to analyze the HDAC9-associated inflammation and tumor progression. Immune cells and cytokines in TME or draining lymph nodes were quantified by flow cytometry and quantitative reverse transcription-PCR. The antigen presentation and CD8⁺ T cell priming by tumor-infiltrating dendritic cells (DCs) were evaluated in vitro and in vivo. HDAC9-associated inflammation was investigated in a mouse model with dextran sulfate sodium-induced colitis. Correlation of HDAC9 with CD8⁺ expression was assessed in tissue sections from patients with non-small cell lung cancer. RESULTS:HDAC9 deficiency promoted tumor progression by decreasing the CD8⁺ DC infiltration of the TME. Compared with wild-type mice, the tumor-infiltrating DCs of Hdac9 mice displayed impaired cross-presentation of tumor antigens and cross-priming of CD8⁺ T cells. Moreover, HDAC9 expression was significantly positively correlated with CD8⁺ cell counts in human lung cancer stroma samples. CONCLUSIONS:HDAC9 deficiency decreased inflammation and promoted tumor progression by decreasing CD8⁺ DC infiltration of the TME. HDAC9 expression in the tumor stroma may represent a promising biomarker to predict the therapeutic responses of patients receiving CD8⁺ T cell-dependent immune treatment regimens.

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