Project Summary The utility of drugs that regulate epigenetic patterns in cells are gaining traction in oncology in part due to reported cytostatic effect on tumor cells. While much attention is on tumor cells, little is known about their effects on immune cells that are recruited to the tumor microenvironment. This issue is of particular importance when considering the increasing appeal of immunotherapeutic drugs which show promising results in cancer patients where other therapies have failed. Such therapeutic outcomes are attributed to re-invigoration of effector components of immune cells. Thus agents which have the potential to promote immune cell function while dampening inhibitory mechanisms within the tumor microenvironment are predicted to promote therapeutic benefits. In this regard, we have found that an inhibitor targeting select histone deacetylases, and an inhibitor of the BET family of bromodomain protein exhibit remarkable immune-modulating effects that support improved immune function. The current proposal will build on these findings to understand how these drugs work, and how these unique properties can be leveraged for treatment of non-small cell lung cancer using rational combinatorial drug regimen. Thus, the following aims are proposed: (1) To understand the effect of ACY241 and JQ1 on global gene networks and epigenetic footprints in tumor- associated immune cell subsets. (2) To evaluate the therapeutic potential of ACY241 and JQ1 as partner agents in combinatorial therapy for non-small cell lung cancer (NSCLC) using genetically engineered mouse model (GEMM). (3) To evaluate the effects of novel drug combinations tested in GEMM on ex-vivo propagated patient tumor cultures as a gauge for clinical applicability.