Transcriptional repression by HDAC3 mediates T cell exclusion from <i>Kras</i> mutant lung tumors.

Abstract

Histone Deacetylase 3 (HDAC3) function in vivo is nuanced and directed in a tissue-specific fashion. The importance of HDAC3 in <i>Kras</i> mutant lung tumors has recently been identified, but HDAC3 function in this context remains to be fully elucidated. Here, we identified HDAC3 as a lung tumor cell-intrinsic transcriptional regulator of the tumor immune microenvironment. In <i>Kras</i> mutant lung cancer cells, we found that HDAC3 is a direct transcriptional repressor of a cassette of secreted chemokines, including <i>Cxcl10</i>. Genetic and pharmacological inhibition of HDAC3 robustly up-regulated this gene set in human and mouse <i>Kras</i>, <i>LKB1</i> (KL) and <i>Kras</i>, <i>p53</i> (KP) mutant lung cancer cells through an NF-κB/p65-dependent mechanism. Using genetically engineered mouse models, we found that HDAC3 inactivation in vivo induced expression of this gene set selectively in lung tumors and resulted in enhanced T cell recruitment at least in part via <i>Cxcl10</i>. Furthermore, we found that inhibition of HDAC3 in the presence of Kras pathway inhibitors dissociated <i>Cxcl10</i> expression from that of immunosuppressive chemokines and that combination treatment of entinostat with trametinib enhanced T cell recruitment into lung tumors in vivo. Finally, we showed that T cells contribute to in vivo tumor growth control in the presence of entinostat and trametinib combination treatment. Together, our findings reveal that HDAC3 is a druggable endogenous repressor of T cell recruitment into <i>Kras</i> mutant lung tumors.