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Targeting UHRF1 in combinational immunotherapy

联合免疫疗法中靶向 UHRF1

基本信息

批准号：
9763378
负责人：
Qijing Li
金额：
$ 47.37万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9763378
关键词：
Antiviral Agents Biological Markers 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 Immunosuppressive Agents 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 PDCD1LG1 gene PHD Finger Patients Population Production Readiness Regulation Regulatory T-Lymphocyte Repression Resistance Ring Finger Domain Role SLEB2 gene 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 combat genome-wide histone modification immune checkpoint blockade improved inhibitor/antagonist melanoma neoplastic cell novel novel marker novel therapeutics overexpression preclinical efficacy prototype recruit response side effect small molecule success transmission process tumor tumor microenvironment

项目摘要

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