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

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 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.