J Cancer 2019; 10(23):5638-5645. doi:10.7150/jca.34471
Histone deacetylase inhibition up-regulates MHC class I to facilitate cytotoxic T lymphocyte-mediated tumor cell killing in glioma cells
1. Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
2. State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, China.
# Ting Sun and Yanyan Li are equal to the work.
Sun T, Li Y, Yang W, Wu H, Li X, Huang Y, Zhou Y, Du Z. Histone deacetylase inhibition up-regulates MHC class I to facilitate cytotoxic T lymphocyte-mediated tumor cell killing in glioma cells. J Cancer 2019; 10(23):5638-5645. doi:10.7150/jca.34471. Available from http://www.jcancer.org/v10p5638.htm
Background: Immune cells recognize tumor antigens presented on major histocompatibility complex class I (MHC-I) molecule. Increase of MHC-I molecular expression makes tumor cells more susceptible to lysis by immune cells.
Methods: Tumor lysate vaccine was prepared to damage glioma cells including cell lines and primary cultured cells from surgical samples. The enhanced effect of histone deacetylase inhibitors (HDACi) to tumor lysate vaccine was observed. The expressions of MHC-I pathway molecules were detected by flow cytometry and western blot after HDACi treatment. Cell apoptosis and cell lysis were measured following blocking cytotoxic T lymphocyte (CTL) pathway. Tumor size and mice survival were analyzed in combinative treatment with HDACi and tumor lysate.
Results: HDACi up-regulated the expressions of MHC-I pathway molecules, and enhanced the recognition and killing of immune cells, which was activated by tumor lysate. Activated antigen specific immune responses regulated CTL activity, and HDACi promoted immune response through cytotoxic effect of CTL. Anti-tumor effect of tumor lysate pulse immunogenicity in vivo was elevated by HDACi due to up-regulation of antigen presentation.
Conclusions: Our study showed that HDACi enhanced recognition of glioma cell by immune cells and sensitivity of tumor immunotherapy, and improved the anti-tumor effect of tumor lysate vaccine through activating CTL immune response. These pharmacological molecular mechanisms of increasing immune recognition suggest that epigenetic modulation is a promising strategy for sensitizing immunotherapy for glioma treatment.
Keywords: Histone deacetylase inhibitors, Antigen presentation, Cytotoxic T lymphocytes, Immune recognition