HDAC6 inhibitor ACY241 evokes transcriptional changes in tumor-associated T cells and macrophages

While HDAC inhibitors have shown promise in hematologic cancers, their efficacy remains limited in solid cancers. In the present study, we evaluated the immunomodulatory properties of the HDAC6 inhibitor, Citarinostat (ACY241) on lung tumor immune compartment in Kras and p53 mutant autochthonous murine model of non-small cell lung cancer. Tumor-bearing mice were treated with ACY241 or vehicle as controls after which tumor-associated effector T cells (CD3+CD25low/-) macrophages CD11b+CD11cdimGr-1-) were sorted from lung tumors and subjected to RNA-sequencing. We found that the effect of ACY241 was most pronounced on macrophages compared to T cells. Over 4, 450 genes were differentially expressed in T cells while over 5, 650 genes were differentially regulated in tumor-associated macrophages upon ACY 241 treatment. Among the most upregulated genes are those encoding costimulatory molecules Tnfrsf9, Cd40, Cd80, Cd83; MHC proteins H2-Ab1, H2-DMb1, as well as related proteins Cd1d1, Cd74, Ctsa, and Tpp1. A number of chemokine genes such as Cxcl12, Ccl4, and Ccl22 were also differentially expressed. Furthermore, several downregulated gene transcripts include Tgfbr3, Cd274, Nos, Pdcd4, and Tnfsf10. Our findings suggest that HDAC6 while primarily considered a cytoplasmic protein, has measurable transcriptional activity that is revealed through its inhibition in tumor-associated immune cell subsets.. Tumor-associated macrophages and conventional T cells were isolated from lung tumors of Kras and p53 mutant genetically engineered mouse model of non-small cell lung cancer. Samples were processed for bulk RNA-sequencing.