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.

项目总结/摘要 本申请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）的治疗和转移，并开发新的治疗方法， HNSCC。HNSCC患者，特别是人乳头瘤病毒（HPV）阴性的HNSCC患者， 5-与乳腺癌和结直肠癌相比，因此，需要开发新的有效疗法， 为HNSCC患者开发。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， 组蛋白去甲基化酶KDM 4A作为一个关键的表观遗传因子，刺激了侵袭基因的转录， 通过消除抑制性H3 K9 me 3标记促进HNSCC侵袭和转移。为了进一步证实 KDM 4A是HNSCC治疗的重要靶点，我们利用4-硝基喹啉1-氧化物（4-NQO）- 诱导的HNSCC小鼠模型，其完全模拟HNSCC的发展和淋巴结转移， 同源肿瘤免疫微环境。我们发现KDM 4A的特异性缺失显著抑制了 HNSCC侵袭性生长和淋巴结转移。我们的RNA-seq分析发现，KDM 4A消融 显著抑制与细胞迁移和上皮间充质相关的基因表达， 在原发性HNSCC中，这证实了我们以前的发现。出乎意料的是， 在来自KDM 4A敲除小鼠的原代HNSCC组织中，具有免疫应答的HNSCC表达强烈上调。 免疫组化结果显示，抑制KDM 4A可增加HNSCC中CD 8 + T细胞的浸润。 最近，靶向PD 1/PD-L1的免疫检查点抑制剂在几种固体药物中取得了巨大成功。 肿瘤包括HNSCC。尽管抗PD 1疗法已被批准用于治疗复发性或转移性疾病， HNSCC的客观缓解率低于20%，表明HNSCC细胞可能具有内在耐药性 检查站封锁。因此，逆转HNSCC细胞的低免疫原性已经变得越来越重要。 癌症免疫治疗的必要性考虑到KDM 4A在染色质可及性中的关键作用， DNA复制，我们假设靶向KDM 4A不仅抑制了侵袭性基因的表达， 还通过诱导DNA复制有效激活肿瘤固有免疫并诱导CD 8 + T细胞浸润 应力为了验证我们的假设，我们将提出以下具体目标：1）确定KDM 4A消融是否 抑制侵袭性基因的表达，激活肿瘤细胞内在免疫; 2）探索 靶向KDM 4A损害DNA复制并通过诱导肿瘤细胞内在免疫应答来激活肿瘤细胞内在免疫应答。 复制应激;和3）确定靶向KDM 4A是否可以帮助克服HNSCC对PD的抗性。 1通过募集和激活CD 8 + 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的治疗策略。