The Inhibition of HNSCC Growth and Metastasis by Targeting KDM4A

通过靶向 KDM4A 抑制 HNSCC 的生长和转移

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该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鳞状细胞癌 (HNSCC) 和转移，并开发新的治疗方法 HNSCC。 HNSCC 患者，特别是人乳头瘤病毒 (HPV) 阴性 HNSCC 患者的总体表现较差与乳腺癌和结直肠癌相比的 5 年生存率。因此，需要新的有效疗法专为 HNSCC 患者开发。新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化酶 KDM4A 作为关键的表观遗传因子，刺激入侵基因的转录通过消除抑制性 H3K9me3 标记促进 HNSCC 侵袭和转移。为了进一步确认 KDM4A是HNSCC治疗的重要靶点，我们利用了4-硝基喹啉1-氧化物(4-NQO)- 诱导小鼠 HNSCC 模型，完全模拟 HNSCC 的发展和淋巴结转移同基因肿瘤免疫微环境。我们发现KDM4A的特异性缺失显着抑制 HNSCC 侵袭性生长和淋巴结转移。我们的 RNA-seq 分析发现 KDM4A 消融显着抑制与细胞迁移和上皮间质相关的基因表达原发性 HNSCC 的转变，证实了我们之前的发现。出乎意料的是，一组相关基因在 KDM4A 敲除小鼠的原发性 HNSCC 组织中，免疫反应显着上调。免疫染色显示，KDM4A 的抑制增加了 HNSCC 中 CD8+ T 细胞的浸润。近年来，针对PD1/PD-L1的免疫检查点抑制剂在多个实体瘤领域取得了巨大成功。肿瘤，包括 HNSCC。尽管抗PD1疗法已被批准用于治疗复发性或转移性 HNSCC，客观缓解率低于20%，表明HNSCC细胞可能具有本质耐药性到检查站封锁。因此，逆转 HNSCC 细胞的低免疫原性已变得越来越重要对正在进行的癌症免疫治疗至关重要。鉴于 KDM4A 在染色质可及性中的关键作用 DNA复制，我们假设靶向KDM4A不仅抑制入侵基因的表达，而且还可有效激活肿瘤内在免疫并通过诱导 DNA 复制诱导 CD8+ T 细胞浸润压力。为了检验我们的假设，我们将提出以下具体目标：1）确定KDM4A是否被消融抑制 HNSCC 侵袭基因的表达并激活肿瘤细胞内在免疫； 2）探索靶向 KDM4A 通过诱导损伤 DNA 复制并激活肿瘤细胞内在免疫反应复制压力； 3) 确定靶向 KDM4A 是否有助于克服 HNSCC 对 PD-的耐药性 1 通过招募和激活 CD8+ T 细胞进行阻断治疗。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。