The immunomodulatory properties of the HDAC6 inhibitor ACY241 supports robust anti-tumor response in NSCLC when coupled with the chemotherapy drug Oxaliplatin

Abstract

Background: Durable treatments that benefit a wide pool of patients remain elusive for Non-small cell lung cancer (NSCLC). The success of immunotherapy in a subset of NSCLC patients highlights the potential contribution of immune response to anti-tumor immunity while underscoring 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 effects of the HDAC6 inhibitor, ACY241 on lung tumor immune compartment with the goal of understanding the scope of its immunomodulatory properties and its therapeutic potential in combination with Oxaliplatin. Methods: Lung adenocarcinoma-bearing mice were treated with ACY241 or vehicle after which the proportions and phenotype of tumor-associated T cells and macrophages were evaluated by comprehensive flow cytometric analysis. Bulk RNA-sequencing was also conducted on both cellular subsets to interrogate the transcriptomic changes associated with ACY241 treatment relative to vehicle controls. In vivo drug efficacy study was performed by administration of ACY241 and/or Oxaliplatin and assessing tumor growth and survival of tumor-bearing mice. Ex vivo functional studies was performed to assess tumor-associated T cell effector function as it correlates with measured outcomes. Results: We demonstrate that ACY241 promotes increased presence of T and NK cells in the lung tumors of treated mice. The tumor-associated T cells under ACY241 treatment displayed enhanced activation, proliferation, and effector profile. In addition, tumor-associated macrophages exhibited increased expression of MHC and co-stimulatory molecules while expression of inhibitory ligands were reduced. RNA-sequencing of both tumor-associated T cells and macrophages revealed significant genomic changes in both subsets that is consistent with ACY241-mediated enhancement of immune priming. These broad immunomodulatory properties of ACY241 were associated with significantly enhanced tumor-associated T cell effector functionality, robust anti-tumor response, and significantly prolonged survival of NSCLC-bearing mice when combined with the chemotherapy drug Oxaliplatin. Conclusion: Collectively, our studies highlight the broad immunomodulatory effect of ACY241 as a promising HDAC6 inhibitor which coupled with Oxaliplatin promotes robust therapeutic outcomes in a pre-clinical model of NSCLC, providing compelling rationale for the clinical testing of this novel combinatorial regimen in NSCLC.

Regulating Histone Deacetylase Signaling Pathways of Myeloid-Derived Suppressor Cells Enhanced T Cell-Based Immunotherapy

“…ACY241 induced antigen-specific memory T cells via the upregulation of transcription regulators such as Bcl-6, Eomes, HIF-1, and T-bet associated with the activation of downstream AKT/mTOR/p65 pathway ( 95 ). More recently, ACY241 induced accumulation of lung tumor-infiltrating T and NK cells while it reduced Tregs in non-small cell lung cancer (NSCLC)-bearing treated mice ( 103 ). Also, tumor-associated macrophages showed increased expression in MHC and co-stimulatory molecules such as CD80, CD86, and CD40 while it reduced inhibitory ligands like PD-L1 and PD-L2.…”

“…Also, tumor-associated macrophages showed increased expression in MHC and co-stimulatory molecules such as CD80, CD86, and CD40 while it reduced inhibitory ligands like PD-L1 and PD-L2. ACY241 in combination with Oxaliplatin – a chemotherapy drug-induced T cells effector function, significant anti-tumor response, and increased survival of NSCLC bearing mice ( 103 ). This highlights the mechanisms by which ACY241 confers anti-tumor activity through regulating immune responses in patients and suggests a rationale for its clinical use in combination with other therapies in several cancers.…”