Transcriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors [KL LJE1 cells p65 KO RNA-seq]

Histone Deacetylase 3 (HDAC3) function in vivo is nuanced and directed in a tissue specific fashion. The importance of HDAC3 in Kras 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 Kras mutant lung cancer cells, we found that HDAC3 is a direct transcriptional repressor of a cassette of secreted chemokines, including Cxcl10. Genetic and pharmacological inhibition of HDAC3 robustly upregulated this gene set in human and mouse Kras, LKB1 (KL) and Kras, p53 (KP) mutant lung cancer cells through an NF-kB/p65-dependent mechanism. Using genetic 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 Cxcl10. Furthermore, we found that inhibition of HDAC3 in the presence of Kras pathway inhibitors dissociated Cxcl10 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 Kras mutant lung tumors.