HDAC3 Inhibition Promotes Antitumor Immunity by Enhancing CXCL10-Mediated Chemotaxis and Recruiting of Immune Cells

It is generally believed that histone deacetylase (HDAC) inhibi-tors, which represent a new class of anticancer agents, exert their antitumor activity by directly causing cell-cycle arrest and apoptosis of tumor cells. However, in this study, we demonstrated that class I HDAC inhibitors, such as Entinostat and Panobinostat, effectively suppressed tumor growth in immunocompetent but not immuno-deficient mice. Further studies with Hdac1, 2, or 3 knockout tumor cells indicated that tumor-specific inactivation of HDAC3 sup-pressed tumor growth by activating antitumor immunity. Specif-ically, we found that HDAC3 could directly bind to promotor regions and inhibit the expression of CXCL9, 10, and 11 chemo- kines. Hdac3-deficient tumor cells expressed high levels of these chemokines, which suppressed tumor growth in immunocompe-tent mice by recruiting CXCR3 thorn T cells into the tumor microen-vironment (TME). Furthermore, the inverse correlation between HDAC3 and CXCL10 expression in hepatocellular carcinoma tumor tissues also suggested HDAC3 might be involved in antitu-mor immune regulation and patient survival. Thus, our studies have illustrated that HDAC3 inhibition suppresses tumor growth by enhancing immune cell infiltration into the TME. This antitumor mechanism may be helpful in guiding HDAC3 inhibitor-based treatment.

Automated summary

This study demonstrates that class I HDAC inhibitors suppress tumor growth by enhancing anti-tumor immunity, contrary to previous belief that they directly affect tumor cell cycle and apoptosis.