The Inhibition of HNSCC Growth and Metastasis by Targeting KDM4A

通过靶向 KDM4A 抑制 HNSCC 的生长和转移

• 批准号: 10442655
• 负责人: CUN-YU WANG
• 金额: $ 39.34万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442655
• 关键词: Ablation; Adjuvant; CD8-Positive T-Lymphocytes; Chromatin; Colorectal Cancer; DNA Damage; DNA biosynthesis; DNA replication fork; Development; Epigenetic Process; Epithelial; Excision; Exhibits; Gene Activation; Gene Expression; Genes; Genetic Transcription; Genomics; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Human Papillomavirus; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Impairment; Infiltration; Interferon Type I; Knockout Mice; Malignant Epithelial Cell; Malignant Neoplasms; Mesenchymal; Metastatic Neoplasm to Lymph Nodes; Molecular Genetics; Mutation; Neck Cancer; Neoplasm Metastasis; Nitroquinolines; Operative Surgical Procedures; Oral cavity; Oropharyngeal; Oxides; PD-1 blockade; PD-1/PD-L1; Patients; Pharmacology; Play; Production; Recurrence; Resistance; Role; S phase; Solid Neoplasm; Survival Rate; T-Lymphocyte; Testing; Tissues; Transcriptional Activation; Tumor Cell Invasion; Tumor Immunity; Tumor-infiltrating immune cells; Work; anti-PD1 therapy; cancer cell; cancer immunotherapy; cell motility; chemokine; chemoradiation; cytotoxic; effective therapy; histone demethylase; histone methylation; immune checkpoint; immune checkpoint blockade; immunogenicity; improved; lymph nodes; malignant breast neoplasm; melanoma; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; objective response rate; pressure; public health relevance; recruit; replication stress; standard care; success; transcriptome sequencing; tumor; tumor-immune system interactions

Project Summary/Abstract The long-term objectives of this application are to understand how epigenetic factors control the invasive growth and metastasis of head and neck squamous cell carcinoma (HNSCC) and to develop novel therapeutics for HNSCC. Patients with HNSCC, particularly human papillomavirus (HPV)-negative HNSCC, exhibit poor overall 5-year survival rates compared to breast and colorectal cancers. Therefore, novel effective therapies need to be developed for HNSCC patients. Emerging evidence suggests that histone methylation plays a critical role in activation of gene transcription in HNSCC by regulating chromatin accessibility. We have identified that the histone demethylase KDM4A as a key epigenetic factor, stimulated the transcription of the invasive genes to promote HNSCC invasion and metastasis by erasing repressive H3K9me3 marks. To further confirm that KDM4A is an important target for HNSCC treatment, we took advantage of the 4-nitroquinoline 1-oxide (4-NQO)- induced mouse model of HNSCC, which fully simulates HNSCC development and lymph node metastasis in a syngeneic tumor immune microenvironment. We found that the specific deletion of KDM4A significantly inhibited HNSCC invasive growth and lymph node metastasis. Our RNA-seq analysis found that KDM4A ablation significantly suppressed the gene expression associated with cell migration and epithelial mesenchymal transition in primary HNSCC, which confirmed our previous findings. Unexpectedly, a set of genes associated with immune response was robustly upregulated in primary HNSCC tissues from KDM4A knockout mice. Immunostaining revealed that the inhibition of KDM4A increased the infiltration of CD8+ T cells in HNSCC. Recently, immune checkpoint inhibitors targeting PD1/PD-L1 have achieved great success in several solid tumors including HNSCC. Although anti-PD1 therapy has been approved for treating recurrent or metastatic HNSCC, the objective response rate is less than 20%, indicating that HNSCC cells might be intrinsically resistant to checkpoint blockades. Thus, reversing the hypo-immunogenicity of HNSCC cells has become increasingly imperative to ongoing cancer immunotherapy. Given the critical role of KDM4A in chromatin accessibility and DNA replication, we hypothesize that targeting KDM4A not only inhibits the expression of invasive genes, but also potently activate tumor-intrinsic immunity and induce CD8+ T cell infiltration by inducing DNA replication stress. To test our hypothesis, we will propose the following specific aims: 1) Determine whether KDM4A ablation inhibits the expression of invasive genes and activates tumor cell-intrinsic immunity in HNSCC; 2) Explore targeting KDM4A impairs DNA replication and activates tumor cell-intrinsic immune responses by inducing replication stress; and 3) Determine whether targeting KDM4A can help to overcome HNSCC resistance to PD- 1 blockade therapy by recruiting and activating CD8+ T cells. The results from our studies might help us to develop novel therapeutic strategies for treating head and neck cancer.

项目摘要/摘要 本应用程序的长期目标是了解表观遗传因素如何控制侵入性生长 头和颈部鳞状细胞癌（HNSCC）的转移，并开发新的治疗剂 HNSCC。 HNSCC患者，尤其是人乳头瘤病毒（HPV）阴性HNSCC的患者总体较差 与乳腺癌和结直肠癌相比，5年生存率。因此，新颖的有效疗法需要 为HNSCC患者开发。新兴的证据表明，组蛋白甲基化在 通过调节染色质的可及性来激活HNSCC中基因转录。我们已经确定 组蛋白去甲基酶KDM4A作为关键的表观遗传因子，刺激了侵入性基因的转录 通过消除抑制性H3K9me3标记来促进HNSCC入侵和转移。进一步确认 KDM4A是HNSCC治疗的重要靶标，我们利用了4-硝基喹啉1-氧化物（4-NQO） - 诱导的HNSCC小鼠模型，该模型完全模拟了HNSCC的发育和淋巴结转移 合成性肿瘤免疫微环境。我们发现KDM4A的特定缺失显着抑制 HNSCC侵入性生长和淋巴结转移。我们的RNA-seq分析发现KDM4A消融 显着抑制了与细胞迁移和上皮间质有关的基因表达 主要HNSCC的过渡，证实了我们以前的发现。出乎意料的是，一组相关的基因 在KDM4A敲除小鼠的原代HNSCC组织中，具有免疫反应的强烈上调。 免疫染色表明，KDM4A的抑制增加了HNSCC中CD8+ T细胞的浸润。 最近，针对PD1/PD-L1的免疫检查点抑制剂在几种固体中取得了巨大成功 包括HNSCC在内的肿瘤。尽管抗PD1治疗已被批准用于治疗复发或转移性 HNSCC的客观响应率小于20％，表明HNSCC细胞可能具有内在的抗性 进行检查点封锁。因此，逆转HNSCC细胞的低不良生成性已经越来越多 对持续的癌症免疫疗法必须进行。考虑到KDM4A在染色质访问性中的关键作用和 DNA复制，我们假设靶向KDM4A不仅抑制了侵入性基因的表达，而且抑制 还可以通过诱导DNA复制来激活肿瘤中的免疫力并诱导CD8+ T细胞浸润 压力。为了检验我们的假设，我们将提出以下特定目的：1）确定KDM4A是否消融 抑制侵入性基因的表达并激活HNSCC中肿瘤细胞中性免疫。 2）探索 靶向KDM4A会损害DNA的复制并通过诱导肿瘤细胞中的免疫反应激活肿瘤细胞中性免疫反应 复制应力； 3）确定靶向KDM4A是否可以帮助克服HNSCC对PD-的抗性 1通过募集和激活CD8+ T细胞的封锁治疗。我们研究的结果可能会帮助我们 制定用于治疗头颈癌的新型治疗策略。