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: 10615200
• 负责人: CUN-YU WANG
• 金额: $ 39.74万
• 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/10615200
• 关键词: Ablation; Adjuvant; CD8-Positive T-Lymphocytes; Cells; Chromatin; Colorectal Cancer; DNA Damage; DNA Replication Induction; DNA biosynthesis; DNA replication fork; Development; Epigenetic Process; Epithelium; 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; Invaded; Knockout Mice; Malignant Neoplasms; Mesenchymal; Metastatic Neoplasm to Lymph Nodes; Molecular; Mutation; Neck; Neck Cancer; Neoplasm Metastasis; Nitroquinolines; Operative Surgical Procedures; Oral cavity; Oropharyngeal; Oxides; PD-1 blockade; PD-1/PD-L1; Patients; Play; Probability; Production; Recurrence; Resistance; Role; S phase; Solid Neoplasm; Survival Rate; T cell infiltration; T-Lymphocyte; Testing; Tissues; Transcriptional Activation; Tumor Cell Invasion; Tumor Immunity; Tumor Promotion; 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; pharmacologic; 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 这项应用的长期目标是了解表观遗传因素如何控制侵袭性生长。 头颈部鳞状细胞癌(HNSCC)的转移和转移以及开发新的治疗方法 HNSCC。HNSCC患者，特别是人类乳头瘤病毒(HPV)阴性的HNSCC患者总体表现较差 与乳腺癌和结直肠癌相比，5年生存率。因此，需要新的有效的治疗方法 为HNSCC患者开发的。新出现的证据表明，组蛋白甲基化在 通过调节染色质可及性激活HNSCC中的基因转录。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，刺激侵袭基因的转录 通过清除抑制性H3K9me3标记促进HNSCC的侵袭和转移。为了进一步证实 KDM4A是治疗HNSCC的一个重要靶点，我们利用了4-硝基喹啉-1-氧化物(4-NQO)- 诱导的小鼠HNSCC模型，完全模拟HNSCC的发展和淋巴转移。 同基因肿瘤免疫微环境。我们发现KDM4A的特异性缺失显著抑制了 HNSCC的侵袭性生长和淋巴结转移。我们的RNA-seq分析发现KDM4A消融 显著抑制与细胞迁移和上皮间质相关的基因表达 原发HNSCC的转变，证实了我们之前的发现。出乎意料的是，一组与 在KDM4A基因敲除小鼠的原代HNSCC组织中，免疫应答显著上调。 免疫组织化学染色显示，抑制KDM4A可增加CD8+T细胞在HNSCC中的浸润。 最近，针对PD1/PD-L1的免疫检查点抑制剂在几个固体中取得了巨大的成功 肿瘤包括HNSCC。尽管抗PD1疗法已被批准用于治疗复发或转移 HNSCC的客观应答率不到20%，提示HNSCC细胞可能具有内在抗性 设置检查站封锁。因此，逆转HNSCC细胞的低免疫原性已变得越来越多 正在进行的癌症免疫治疗势在必行。鉴于KDM4A在染色质可及性和 DNA复制，我们假设靶向KDM4A不仅抑制侵袭性基因的表达，而且 还可通过诱导DNA复制，有效激活肿瘤内源性免疫，诱导CD8+T细胞浸润 压力。为了验证我们的假设，我们将提出以下具体目标：1)确定KDM4A消融是否 抑制HNSCC侵袭基因表达，激活肿瘤细胞内源性免疫；2)探索 靶向KDM4A抑制DNA复制并激活肿瘤细胞内源性免疫应答 复制应激；以及3)确定靶向KDM4A是否有助于克服HNSCC对PD- 1通过募集和激活CD8+T细胞阻断治疗。我们的研究结果可能会帮助我们 开发治疗头颈癌的新治疗策略。