Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non–Small Cell Lung Cancer

Abstract

Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T cell activation and improved function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

“…They are the only domains, which bind specifically to histone acetylation marks (Jain & Barton, 2017). Even though combined treatment with HDAC and BET inhibitors (BETi) revealed additive or synergistic effects in several cancer entities, such as cutaneous T-cell lymphoma, neuroblastoma, glioblastoma, non-small cell lung cancer, adenocarcinoma, and colon cancer (Mazur et al, 2015;Shahbazi et al, 2016;Adeegbe et al, 2017;Meng et al, 2018;Rajendran et al, 2019;Zhao et al, 2019), so far only few studies described the mono-and combined treatment options with BETis in GCTs. Even though combined treatment with HDAC and BET inhibitors (BETi) revealed additive or synergistic effects in several cancer entities, such as cutaneous T-cell lymphoma, neuroblastoma, glioblastoma, non-small cell lung cancer, adenocarcinoma, and colon cancer (Mazur et al, 2015;Shahbazi et al, 2016;Adeegbe et al, 2017;Meng et al, 2018;Rajendran et al, 2019;Zhao et al, 2019), so far only few studies described the mono-and combined treatment options with BETis in GCTs.…”

“…Recently, the anti-cancer efficacy of inhibitors against the bromodomain and extra-terminal domain-containing (BET) protein family have been evaluated in several cancers, such as prostate, breast, colon, intestine, pancreas, liver, lung, brain, oral squamous cell carcinoma, and leukemias (Sahai et al, 2016;Saenz et al, 2017;Xu & Vakoc, 2017;Sahni & Keri, 2018;Zhang et al, 2018;Baldan et al, 2019). Even though combined treatment with HDAC and BET inhibitors (BETi) revealed additive or synergistic effects in several cancer entities, such as cutaneous T-cell lymphoma, neuroblastoma, glioblastoma, non-small cell lung cancer, adenocarcinoma, and colon cancer (Mazur et al, 2015;Shahbazi et al, 2016;Adeegbe et al, 2017;Meng et al, 2018;Rajendran et al, 2019;Zhao et al, 2019), so far only few studies described the mono-and combined treatment options with BETis in GCTs. The amount of transcripts of bromodomain-containing genes increases the higher the GCT stage is (Gashaw et al, 2005), indicating bromodomains being an interesting target for GCT treatment.…”

Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma

“…13 We therefore next examined whether ACY-241, anti-PD-L1, or their combination triggers the generation of MM-specific cytotoxic T lymphocyte (CTLs) ex vivo . MM patient BM C8 + T cells (n=7) were co-cultured with autologous pDCs (pDC:T; 1:10 ratio) in the presence of anti-PD-L1 Ab, ACY-241, or ACY-241 plus anti-PD-L1 Ab for 5 days.…”

The next‐generation BET inhibitor, PLX51107, delays melanoma growth in a CD8‐mediated manner

“…, as well as immune-mediated diseases (Chen et al, 2016;Klein et al, 2016;Sun et al, 2015). BETi also impact pro-and anti-inflammatory responses by altering cytokine expression, inducing pro-inflammatory macrophages, affecting dendritic cell (DC) activation, and regulating T-cell activation and differentiation (Adeegbe et al, 2017;Das et al, 2015;Kagoya et al, 2016;Qiao & Ivashkiv, 2015;Toniolo et al, 2015;Xu & Vakoc, 2014). Despite their efficacy, first-generation BETi (JQ1, iBET762, and OTX015) have hematologic dose-limiting toxicities at pharmacologically effective doses in mice and humans (Amorim et al, 2016;Berthon et al, 2016;Lee et al, 2016).…”