Targeting UHRF1 in combinational immunotherapy

联合免疫治疗中的靶向 UHRF1

• 批准号: 10308390
• 负责人: XIAO-FAN WANG
• 金额: $ 46.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-11 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308390
• 关键词: Biological Markers; CTLA4 blockade; CTLA4 gene; CXCL9 gene; Cancer Patient; Cancer cell line; Cell Aging; Cells; Combination immunotherapy; Combined Modality Therapy; Consensus; DNA; Daughter; Dendritic Cells; Disease remission; Epigenetic Process; Foundations; Gene Activation; Genes; Genetic; Immune; Immune system; Immunosuppression; Impairment; Individual; Interferon Type I; Interferon Type II; Interferons; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mothers; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; Nuclear Protein; Oncogenes; PHD Finger; Patients; Population; Production; Readiness; Regulation; Regulatory T-Lymphocyte; Repression; Resistance; Ring Finger Domain; Role; Stromal Cells; Surface; T-Cell Activation; T-Lymphocyte; T-cell inflamed; Testing; Therapeutic; Tumor Suppressor Proteins; Ubiquitin; Viral Physiology; Virus; anti-CTLA4; anti-PD1 therapy; anti-tumor immune response; cancer cell; cancer immunotherapy; cancer therapy; cancer type; chemokine; clinical efficacy; epigenetic silencing; genome-wide; histone modification; immune checkpoint blockade; improved; inhibitor; lung cancer cell; melanoma; neoplastic cell; novel; novel marker; novel therapeutic intervention; overexpression; preclinical efficacy; programmed cell death ligand 1; programmed cell death protein 1; prototype; recruit; response; side effect; small molecule; success; transmission process; tumor; tumor microenvironment; tumor-immune system interactions

Immune checkpoint blockade therapy has delivered unprecedented success in the treatment of melanoma and lung cancer. However, as exciting as this is, even with combined inhibition of PD-1 and CTLA4, only a portion of cancer patients were observed with objective responses and an even smaller percentage of them reached long term remission. Therefore, it is imperative to identify specific mechanisms that determine the efficacy of checkpoint targeting, and to develop novel therapeutic strategies synergizing with current treatments. Although the mechanism of checkpoint blockade resistance has not been precisely determined by changes in any novel biomarkers, a consensus has been reached that more favorable responses are observed in patients with T cell-inflamed ”hot” tumors. At the molecular level, the inflamed tumor microenvironment is characterized by activation of T and NK cells, effector molecules for cytolytic functions, chemokines for T and NK cell recruitment, type I interferons (IFN-I), and interferon-responsive genes. The anti-virus role of IFN-I was discovered decades ago, whereas its anti-tumor mechanism was more recently elucidated. The emerging scientific premise supports the hypothesis that there exists a plausible strategy to improve the immune “readiness” of a tumor, and to overcome tumor resistance to checkpoint blockade therapy by elevating the level of intratumoral IFN-I. In this regard, our preliminary results show that inhibiting the expression of one epigenetic modifier, ubiquitin like with PHD and ring finger domains 1 (UHRF1), in lung cancer cells dramatically triggers IFN-I responses and ultimately intratumoral T cell accumulation. Surprisingly, UHRF1 deficient tumor cells also become resistant to IFN-I-induced PD-L1 surface expression. Furthermore, genetic deletion of UHRF1 impairs the proliferation and function of regulatory T cells (iTregs), a stromal cell population in the tumor mass that carries out an immunosuppressive function. Taken together, we hypothesize that targeting UHRF1 represents a comprehensive strategy to reverse immunosuppression in the tumor microenvironment. In this study, we will test this hypothesis by three specific aims. Aim 1 will determine molecular mechanisms through which tumoral UHRF1 remodels the tumor microenvironment. Aim 2 will determine the mechanism by which UHRF1 regulates T cell activation. Aim 3 will determine the pre-clinical efficacy of a therapeutic strategy combining UHRF1 suppression and PD-1 or CTLA-4 blockade against lung cancer. Since a small molecule UHRF1 inhibitor prototype has been developed, the success of this project will establish a novel and feasible target for tumor microenvironmental reprogramming, and lay a scientific foundation for combination therapy with checkpoint blockade against lung cancer.

免疫检查点阻断疗法在治疗黑色素瘤方面取得了前所未有的成功 和肺癌。然而，尽管这令人兴奋，即使联合抑制PD-1和CTLA 4， 观察到一部分癌症患者有客观反应， 达到长期缓解。因此，必须确定 检查点靶向的有效性，并开发与目前的治疗策略协同作用的新的治疗策略。 治疗。虽然检查点封锁抵抗的机制还没有被精确地确定 通过任何新的生物标志物的变化，已经达成了一个共识，即更有利的反应是 在T细胞发炎的“热”肿瘤患者中观察到。在分子水平上， 微环境的特征在于T和NK细胞的活化，细胞溶解功能的效应分子， 用于T和NK细胞募集的趋化因子、I型干扰素（IFN-I）和干扰素应答基因。的 IFN-I的抗病毒作用是几十年前发现的，而其抗肿瘤机制是最近才发现的。 阐明。新出现的科学前提支持这样一种假设，即存在一种合理的策略， 提高肿瘤的免疫“准备状态”，并克服肿瘤对检查点阻断的抗性 通过提高肿瘤内IFN-I的水平进行治疗。在这方面，我们的初步结果显示， 抑制一种表观遗传修饰物，具有PHD和环指结构域1的泛素样的表达 （UHRF 1），在肺癌细胞中显著触发IFN-I应答，并最终在肿瘤内T细胞 积累令人惊讶的是，UHRF 1缺陷肿瘤细胞也对IFN-I诱导的PD-L1产生耐药性 表面表达此外，UHRF 1的基因缺失损害了细胞的增殖和功能。 调节性T细胞（iTcells，iTcells）是肿瘤块中的一种基质细胞群， 免疫抑制功能总而言之，我们假设针对UHRF 1代表了一种 逆转肿瘤微环境中免疫抑制的综合策略。本研究 将通过三个具体目标来检验这一假设。目标1将确定分子机制， 肿瘤UHRF 1重塑肿瘤微环境。目标2将确定 UHRF 1调节T细胞活化。目标3将确定治疗策略的临床前疗效 联合UHRF 1抑制和PD-1或CTLA-4阻断治疗肺癌。因为一个小分子 UHRF 1抑制剂原型已经开发出来，该项目的成功将建立一个新的， 为肿瘤微环境重编程提供可行靶点，为联合应用奠定科学基础 检查点阻断治疗肺癌。