Open AccessHistone deacetylase inhibition promotes intratumoral CD8+ T-cell responses, sensitizing murine breast tumors to anti-PD1
Author(s) -
Tyler R. McCaw,
Mei Li,
Dmytro Starenki,
Mingyong Liu,
Sara J. Cooper,
Rebecca C. Arend,
Andres Forero,
Donald J. Buchsbaum,
Troy D. Randall
Publication year - 2019
Publication title -
cancer immunology, immunotherapy/cancer immunology and immunotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.389
H-Index - 115
eISSN - 1432-0851
pISSN - 0340-7004
DOI - 10.1007/s00262-019-02430-9
Subject(s) - cancer research , histone deacetylase , cd8 , t cell , in vivo , histone deacetylase inhibitor , cytotoxic t cell , cell growth , biology , immune system , chemistry , immunology , in vitro , histone , biochemistry , genetics , microbiology and biotechnology , gene
Histone deacetylase (HDAC) inhibitors impair tumor cell proliferation and alter gene expression. However, the impact of these changes on anti-tumor immunity is poorly understood. Here, we showed that the class I HDAC inhibitor, entinostat (ENT), promoted the expression of immune-modulatory molecules, including MHCII, costimulatory ligands, and chemokines on murine breast tumor cells in vitro and in vivo. ENT also impaired tumor growth in vivo-an effect that was dependent on both CD8 + T cells and IFNγ. Moreover, ENT promoted intratumoral T-cell clonal expansion and enhanced their functional activity. Importantly, ENT sensitized normally unresponsive tumors to the effects of PD1 blockade, predominantly through increases in T-cell proliferation. Our findings suggest that class I HDAC inhibitors impair tumor growth by enhancing the proliferative and functional capacity of CD8 + T cells and by sensitizing tumor cells to T-cell recognition.