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

• Published in: Journal for immunotherapy of cancer Vol. 8; no. 1; p. e000529
• Main Authors: Ning, Yongling, Ding, Jun, Sun, Xiao, Xie, Yewen, Su, Mingming, Ma, Chenglong, Pan, Jie, Chen, Jie, Jiang, Hua, Qi, Chunjian
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.06.2020; BMJ Publishing Group
• Series: Original research
• Subjects: Animals; Antigen Presentation - immunology; Basic Tumor Immunology; Bone marrow; Cancer; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - pathology; CD8-Positive T-Lymphocytes - immunology; Dendritic cells; Dendritic Cells - immunology; Flow cytometry; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histone Deacetylases - physiology; Humans; Immunotherapy; Laboratory animals; Ligands; Lung cancer; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lymphatic system; Lymphocyte Activation - immunology; Lymphocytes; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoclonal antibodies; Neutrophils; Peptides; Repressor Proteins - genetics; Repressor Proteins - metabolism; Repressor Proteins - physiology; Tumor Cells, Cultured; Tumor Microenvironment - immunology; Tumorigenesis; Tumors; Beijing China; United States > US; China; dendritic cells; tumor microenvironment
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2020-000529

BackgroundThe 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.ResultsHDAC9 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.ConclusionsHDAC9 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.