Targeting UHRF1 in combinational immunotherapy

联合免疫治疗中的靶向 UHRF1

• 批准号: 10055773
• 负责人: Qijing Li
• 金额: $ 46.83万
• 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/10055773
• 关键词: Antiviral Agents; 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/antagonist; 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黑色素瘤的治疗中取得了前所未有的成功 然而，尽管这令人兴奋，但即使联合抑制 PD-1 和 CTLA4，也只能起到一定作用。 的癌症患者观察到有客观反应，其中只有更小部分 因此，必须确定决定长期缓解的具体机制。 检查点靶向的功效，并开发与当前协同作用的新治疗策略 尽管检查点封锁抵抗的机制尚未明确确定。 通过任何新生物标志物的变化，已经达成共识，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，发炎的肿瘤。 微环境的特点是 T 细胞和 NK 细胞的激活、细胞溶解功能的效应分子、 T 细胞和 NK 细胞募集的趋化因子、I 型干扰素 (IFN-I) 和干扰素反应基因。 IFN-I 的抗病毒作用是几十年前发现的，而其抗肿瘤机制则是最近才发现的 新兴的科学前提支持这样的假设：存在一种合理的策略。 提高肿瘤的免疫“准备度”，并克服肿瘤对检查点封锁的抵抗力 通过提高肿瘤内 IFN-I 的水平进行治疗 在这方面，我们的初步结果表明： 抑制一种表观遗传修饰剂、泛素的表达，如 PHD 和无名指结构域 1 (UHRF1)，在肺癌细胞中显着触发 IFN-I 反应并最终触发肿瘤内 T 细胞 令人惊讶的是，UHRF1 缺陷的肿瘤细胞也对 IFN-I 诱导的 PD-L1 产生耐药性。 此外，UHRF1 的基因缺失会损害细胞的增殖和功能。 调节性 T 细胞 (iTreg)，肿瘤块中的基质细胞群，执行 总而言之，我们勇敢地说，针对 UHRF1 代表了一种免疫抑制功能。 在这项研究中，我们采用了逆转肿瘤微环境中免疫抑制的综合策略。 将通过三个具体目标来检验这一假设，目标 1 将确定其分子机制。 肿瘤 UHRF1 重塑肿瘤微环境，目标 2 将确定其机制。 UHRF1 调节 T 细胞激活 目标 3 将决定治疗策略的临床前疗效。 结合 UHRF1 抑制和 PD-1 或​​ CTLA-4 阻断来对抗肺癌。 UHRF1抑制剂原型已经开发出来，该项目的成功将建立一种新颖且 肿瘤微环境重编程的可行靶点，为联合用药奠定科学基础 检查点封锁疗法对抗肺癌。