TitleSelective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma.
Publication TypeJournal Article
Year of Publication2020
AuthorsMondello, Patrizia, Tadros Saber, Teater Matt, Fontan Lorena, Chang Aaron Y., Jain Neeraj, Yang Haopeng, Singh Shailbala, Ying Hsia-Yuan, Chu Chi-Shuen, Ma Man Chun John, Toska Eneda, Alig Stefan, Durant Matthew, de Stanchina Elisa, Ghosh Sreejoyee, Mottok Anja, Nastoupil Loretta, Neelapu Sattva S., Weigert Oliver, Inghirami Giorgio, Baselga Jose, Younes Anas, Yee Cassian, Dogan Ahmet, Scheinberg David A., Roeder Robert G., Melnick Ari M., and Green Michael R.
JournalCancer Discov
Volume10
Issue3
Pagination440-459
Date Published2020 03
ISSN2159-8290
KeywordsAnimals, Antigen-Presenting Cells, Antineoplastic Combined Chemotherapy Protocols, B7-H1 Antigen, Cell Line, Tumor, Cell Proliferation, CREB-Binding Protein, Cyclin-Dependent Kinase Inhibitor p21, Epigenome, Genes, MHC Class I, Histocompatibility Antigens Class II, Histone Acetyltransferases, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Immune Checkpoint Inhibitors, Immune System, Interferons, Lymphocytes, Tumor-Infiltrating, Lymphoma, Mice, Mutation, Proto-Oncogene Proteins c-bcl-6, Signal Transduction
Abstract

<p> mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by mutation are direct targets of the BCL6-HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse -mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II-dependent manner, and synergized with PD-L1 blockade in a syngeneic model . Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for -mutant lymphomas. SIGNIFICANCE: We have leveraged the molecular characterization of different types of mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in -mutant cells in tandem with promoting antitumor immunity..</p>

DOI10.1158/2159-8290.CD-19-0116
Alternate JournalCancer Discov
PubMed ID31915197
PubMed Central IDPMC7275250
Grant ListR01 CA178765 / CA / NCI NIH HHS / United States
R35 CA241894 / CA / NCI NIH HHS / United States
R01 CA201380 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
U54 OD020355 / OD / NIH HHS / United States
R01 CA055349 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
P01 CA229100 / CA / NCI NIH HHS / United States
P50 CA192937 / CA / NCI NIH HHS / United States