Presentation of telomerase reverse transcriptase, a self-tumor antigen, is down-regulated by histone deacetylase inhibition.
Histone deacetylases (HDAC) modify the architecture of chromatin, leading to decreased gene expression, an effect that is reversed by HDAC inhibition. The balance between deacetylation and acetylation is central to many biological events including the regulation of cell proliferation and cancer but also the differentiation of immune T cells. The effects of HDAC inhibition on the interaction between antitumor effector T cells and tumor cells are not known. Here, we studied presentation of a universal self-tumor antigen, telomerase reverse transcriptase, in human tumor cells during HDAC inhibition. We found that HDAC inhibition with trichostatin A was associated with a decreased presentation and diminished killing of tumor cells by CTLs. Using gene array analysis, we found that HDAC inhibition resulted in a decrease of genes coding for proteasome catalytic proteins and for tapasin, an endoplasmic reticulum resident protein involved in the MHC class I pathway of endogenous antigen presentation. Our findings indicate that epigenetic changes in tumor cells decrease self-tumor antigen presentation and contribute to reduced recognition and killing of tumor cells by cytotoxic T lymphocytes. This mechanism could contribute to tumor escape from immune surveillance.
Pellicciotta
Ilenia
I
Department of Medicine, Moores Cancer Center, The Laboratory of Immunology, University of California, La Jolla, California92093-0815, USA.
Cortez-Gonzalez
Xochitl
X
Sasik
Roman
R
Reiter
Yoram
Y
Hardiman
Gary
G
Langlade-Demoyen
Pierre
P
Zanetti
Maurizio
M
D017951:Antigen Presentation / Q000187:drug effects*; D000951:Antigens, Neoplasm / Q000187:drug effects / Q000276:immunology*; D001324:Autoantigens / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000276:immunology; D020869:Gene Expression Profiling; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D019098:Telomerase / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D001324:Autoantigens; D015789:HLA-A2 Antigen; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D026901:Membrane Transport Proteins; C107762:tapasin; C012589:trichostatin A; D019098:Telomerase; D046988:Proteasome Endopeptidase Complex