Histone deacetylase inhibition promotes intratumoral CD8+ T-cell responses, sensitizing murine breast tumors to anti-PD1

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2019-12, Vol.68 (12), p.2081-2094
• Main Authors: McCaw, Tyler R., Li, Mei, Starenki, Dmytro, Liu, Mingyong, Cooper, Sara J., Arend, Rebecca C., Forero, Andres, Buchsbaum, Donald J., Randall, Troy D.
• Format: Article
• Language: English
• Subjects: Breast cancer; Cancer Research; CD8 antigen; Cell growth; Cell proliferation; Cell recognition; Chemokines; Gene expression; Histone deacetylase; Immunology; Immunomodulation; Kinases; Lymphocytes T; Medicine; Medicine & Public Health; Oncology; Original Article; PD-1 protein; Tumor cells; Tumors; γ-Interferon
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-019-02430-9

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.