Abstract 637: The class I HDAC inhibitor mocetinostat augments checkpoint inhibitor therapy via direct up regulation of antigen presentation transcriptional programs in tumor cells and increased T-cell clonality in tumors
Authors: Briere David M. , Sudhakar Niranjan , Olson Peter , Christensen Jamie 
Published: July 2017

Mocetinostat is a spectrum-selective class I/IV histone deacetylase (HDAC) inhibitor that augments checkpoint inhibitor therapy through enhanced antigen presentation capacity and a pro-immunogenic shift in the tumor microenvironment (TME). Mocetinostat up-regulated tumor antigen presentation machinery (i.e. major histocompatibility complex (MHC) genes and co-presentation molecules) and programmed cell death-ligand 1 (PD-L1) expression in a panel of non-small cell lung cancer (NSCLC) cell lines. Surprisingly, some of the most highly up regulated genes following mocetinostat treatment were MHC class II genes (~20 fold), which are normally expressed by antigen-presenting cells, but are silenced in most epithelial tissues and solid tumors. To elucidate the molecular mechanisms whereby mocetinostat regulates MHC class I and class II transcriptional programs in tumor cells, we performed chromatin immunoprecipitation DNA sequencing (ChIP-Seq). HDAC2 was detected at the promoters of many mocetinostat-regulated immune pathway genes. Further, mocetinostat treatment increased histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation indicating an induction of active transcription at these loci. Class II transactivator (CIITA) is an interferon gamma (IFNγ)-sensitive regulator of MHC class II gene expression and was one of the top HDAC2/mocetinostat target genes based on ChIP-Seq data. In addition, CIITA and a representative MHC class II gene, HLA-DRA, were synergistically up regulated following mocetinostat and IFNγ treatment. To investigate the impact of Class I HDAC inhibition on the TME, syngeneic mouse tumor models were utilized. Mocetinostat treatment decreased intratumoral immune suppressive T regulatory cells (Tregs) and increased intratumoral CD8+ T cells. To gain additional insight into the functional effects of mocetinostat in the TME, we performed deep sequencing of the T-cell receptor in vehicle, mocetinostat, PD-L1 or combination-treated tumors. Mocetinostat-treated tumor cohorts exhibited increased T-cell clonality which likely reflects expansion of a subset of activated, antigen-specific T cells. Together, these data provide molecular insight into the mechanism whereby mocetinostat augments checkpoint inhibitor therapy by directly regulating tumor antigen presentation and through functional effects on the T cell repertoire.

Citation Format: David M. Briere, Niranjan Sudhakar, Peter Olson, Jamie Christensen. The class I HDAC inhibitor mocetinostat augments checkpoint inhibitor therapy via direct up regulation of antigen presentation transcriptional programs in tumor cells and increased T-cell clonality in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 637. doi:10.1158/1538-7445.AM2017-637