NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model

Liu, Yan; Li, Yuyang; Liu, Shengwu; Adeegbe, Dennis O.; Christensen, Camilla L.; Quinn, Max M.; Dries, Ruben; Han, Song; Buczkowski, Kevin A.; Wang, Xiaoen; Chen, Ting; Gao, Peng; Zhang, Hua; Li, Fēi; Hammerman, Peter S.; Bradner, James E.; Quayle, Steven N.; Wong, Kwok-Kin

doi:10.1158/0008-5472.can-18-0161

Cited by 41 publications

(36 citation statements)

References 44 publications

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“…An HDAC inhibitor suppressed cell proliferation, induced cell cycle arrest and activated Notch signaling in SCLCs in vitro (34). Inhibitor of HDAC6, a cytoplasmic HDAC was shown in a prior study to cause NK cell dependent cytotoxicity in a preclinical SCLC model though the phenotype was not related to NKG2DLs (35).…”

Section: Discussionmentioning

confidence: 98%

Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis

et al. 2021

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Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer with very poor prognosis and limited effective therapeutic options. Most patients are diagnosed at advanced stages, and the exact reason for the aggressive and metastatic phenotype of SCLC is completely unknown.Despite a high tumor mutational burden, responses to immune checkpoint blockade are minimal in SCLC patients. This may reflect defects in immune surveillance. Here we illustrate that evading NK surveillance contributes to SCLC aggressiveness and metastasis, primarily through loss of NK cell recognition of these tumors by reduction of NK-activating ligands (NKG2DL). SCLC primary tumors expressed very low level of NKG2DL mRNA and SCLC lines express little to no surface NKG2DL at the protein level. ChIP-Seq showed NKG2DL loci in SCLC are inaccessible compared to NSCLC, with few H3K27Ac signals. Restoring NKG2DL in preclinical models suppressed tumor growth and metastasis in an NK cell-dependent manner. Likewise, HDAC inhibitor treatment induced NKG2DL expression and led to tumor suppression by inducing infiltration and activation of NK and T cells. Among all the common tumor types, SCLC and neuroblastoma were the lowest NKG2DL-expressing tumors, highlighting a lineage dependency of this phenotype. In conclusion, these data show that epigenetic silencing of NKG2DL results in a lack of stimulatory signals to engage and activate NK cells, highlighting the underlying immune avoidance of SCLC and neuroblastoma.

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Section: Discussionmentioning

confidence: 98%

Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis

et al. 2021

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“…Moreover, our results demonstrating the remarkable efficacy of the combination of PD-L1 blockade with PARP or CHK1 inhibition provide a strong scientific rationale for combining these modalities in clinical trials for patients with SCLC. Further studies will be necessary to carefully interrogate the contribution, if any, of the neoantigen load and other immune cell populations, such as natural killer cells (43), during DDR-mediated T-cell activation. Because prexasertib, olaparib, and other PARP inhibitors are already in clinical trials for SCLC, we expect that these findings have the potential for rapid translation into the clinic.…”

Section: Discussionmentioning

confidence: 99%

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

et al. 2019

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Despite recent advances in the use of immunotherapy, only a minority of patients with small cell lung cancer (SCLC) respond to immune checkpoint blockade (ICB). Here, we show that targeting the DNA damage response (DDR) proteins PARP and checkpoint kinase 1 (CHK1) signifi cantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the antitumor effect of PD-L1 blockade and augmented cytotoxic T-cell infi ltration in multiple immunocompetent SCLC in vivo models. CD8 + T-cell depletion reversed the antitumor effect, demonstrating the role of CD8 + T cells in combined DDR-PD-L1 blockade in SCLC. We further demonstrate that DDR inhibition activated the STING/TBK1/IRF3 innate immune pathway, leading to increased levels of chemokines such as CXCL10 and CCL5 that induced activation and function of cytotoxic T lymphocytes. Knockdown of cGAS and STING successfully reversed the antitumor effect of combined inhibition of DDR and PD-L1. Our results defi ne previously unrecognized innate immune pathway-mediated immunomodulatory functions of DDR proteins and provide a rationale for combining PARP/CHK1 inhibitors and immunotherapies in SCLC. SIGNIFICANCE: Our results defi ne previously unrecognized immunomodulatory functions of DDR inhibitors and suggest that adding PARP or CHK1 inhibitors to ICB may enhance treatment effi cacy in patients with SCLC. Furthermore, our study supports a role of innate immune STING pathway in DDR-mediated antitumor immunity in SCLC.

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“…In one study, selective HDAC6 Inhibitor ACY-1215 and/or BET inhibitor JQ1, as well as vehicle control, were applied to athymic nude mice carrying human small cell lung cancer (SCLC) NCI-H69 xenograft tumors. A gene expression heat map was generated from RNA-seq analysis of these xenograft tumors, which showed that ACY-1215 treatment had limited change with transcription profiling as compared to JQ1 treatment [54].…”

Section: Transcriptomic Effects Of Hdismentioning

confidence: 99%

Mechanism of Action for HDAC Inhibitors—Insights from Omics Approaches

Sun

2019

IJMS

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Histone deacetylase inhibitors (HDIs) are a class of prominent epigenetic drugs that are currently being tested in hundreds of clinical trials against a variety of diseases. A few compounds have already been approved for treating lymphoma or myeloma. HDIs bind to the zinc-containing catalytic domain of the histone deacetylase (HDACs) and they repress the deacetylase enzymatic activity. The broad therapeutic effect of HDIs with seemingly low toxicity is somewhat puzzling when considering that most HDIs lack strict specificity toward any individual HDAC and, even if they do, each individual HDAC has diverse functions under different physiology scenarios. Here, we review recent mechanistic studies using omics approaches, including epigenomics, transcriptomics, proteomics, metabolomics, and chemoproteomics, methods. These omics studies provide non-biased insights into the mechanism of action for HDIs.

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NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model

Cited by 41 publications

References 44 publications

Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis

Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

Mechanism of Action for HDAC Inhibitors—Insights from Omics Approaches

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