Coupling the immunomodulatory properties of the HDAC6 inhibitor ACY241 with Oxaliplatin promotes robust anti-tumor response in Non-small cell lung cancer

Abstract

Abstract Although immunotherapy provides durable therapeutic response in a subset of Non-small cell lung cancer (NSCLC) patients, there is still a need for broadly applicable therapeutic strategies. HDAC inhibitors are a promising class of drugs whose immunomodulatory properties are now being appreciated. In the present study, we evaluated the immunomodulatory properties of the HDAC6 inhibitor, Citarinostat (ACY241) on lung tumor immune compartment and its therapeutic potential in combination with Oxaliplatin. Lung adenocarcinoma-bearing mice were treated with ACY241 or vehicle after which immune profiling and RNA-sequencing were conducted in tumor-associated T cells and macrophages. Ex vivo T cell functional studies, tumor growth assessment and survival of tumor-bearing mice treated with ACY241 and/or Oxaliplatin were also conducted. ACY241 treatment promoted increased presence of T and NK cells as well as activation, proliferation, and effector profile of T cells in the lung tumors of treated mice. Furthermore, tumor-associated macrophages exhibited increased expression of MHC and co-stimulatory molecules while expression of inhibitory ligands were reduced. RNA-sequencing of tumor-associated T cells and macrophages revealed significant genomic changes that is consistent with ACY241-mediated enhancement of immune priming. Finally, ACY241 treatment led to significantly enhanced tumor-associated T cell effector functionality in lung cancer-bearing mice and in patient-derived tumors when combined with the chemotherapy drug Oxaliplatin. Collectively, our studies support ACY241 as a promising HDAC6 inhibitor which coupled with Oxaliplatin promotes robust therapeutic outcomes in a pre-clinical model of NSCLC.