Targeting Tankyrases to Mitigate Immunosuppression and Enhance Cancer Immunotherapy

靶向端锚聚合酶可减轻免疫抑制并增强癌症免疫治疗

• 批准号: 9808268
• 负责人: Steven Hsesheng Lin
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808268
• 关键词: Ablation; Adenocarcinoma Cell; Adenosine Diphosphate Ribose; Antibody Therapy; Attenuated; Binding Sites; Cancer cell line; Catalytic Domain; Cell Proliferation; Cell physiology; Cells; Cervix carcinoma; Down-Regulation; Drug Design; Drug Screening; Effectiveness; Family; Genetic; Genetically Engineered Mouse; Germ-Line Mutation; Homeostasis; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunofluorescence Immunologic; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Infiltration; Link; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic; Mitosis; Modeling; Monoclonal Antibodies; Mus; Mutate; Mutation; Neoplasm Metastasis; PTEN gene; Pathogenesis; Pathway interactions; Patients; Peutz-Jeghers Syndrome; Phenotype; Play; Poly(ADP-ribose) Polymerases; Post-Translational Protein Processing; Process; Proteins; Regulation; Regulatory T-Lymphocyte; Research; Resistance; Role; STK11 gene; Sampling; Squamous cell carcinoma; System; TNKS gene; Tankyrase; Telomerase; Telomere Maintenance; Testing; Tumor Immunity; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Ubiquitination; WNT Signaling Pathway; anti-PD-L1; beta catenin; cancer immunotherapy; cancer therapy; cancer type; clinical translation; cytokine; immune checkpoint blockade; immunoregulation; improved; in vivo; inhibitor/antagonist; insight; lung Carcinoma; member; multicatalytic endopeptidase complex; mutant; neutrophil; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; preclinical study; prognostic; response; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY Liver kinase B1 (LKB1) is a key regulator of cellular energy homeostasis and well known tumor suppressor gene in many cancers, particularly lung cancer, where it is deleted in ~30 percent of tumors. LKB1 suppression or depletion leads to enhanced tumorigenesis, increased immunosuppression, and reduced response to immune checkpoint inhibitors. Despite the importance of LKB1 negative regulation on tumor growth and aggressiveness, there is no known upstream regulator of LKB1. Through a rationally designed drug screen, we identified tankyrases (TNKS; TNKS1, or PARP5A, and TNKS2, or PARP5B), as upstream negative regulators of LKB1. TNKS belong to the closely related members of the poly (ADP-ribose) polymerase (PARP) family that adds ADP-ribose moieties to target proteins using β-NAD+ as substrate, termed PARsylation. PARsylation of target proteins by TNKS typically leads to ubiquination and proteasome degradation, such as AXIN (which sequesters APC/β-catenin in Wnt signaling), PTEN, and telomerase. However, PARsylation of LKB1 does not lead to LKB1 degradation, but inhibit LKB1 activity. Overexpression of TNKS stimulates tumor cellular proliferation in vitro and enhances tumorigenesis in vivo that is LKB1-dependent. Lung tumors (both adenocarcinoma and squamous cell carcinoma) that overexpress TNKS1 in LKB1 expressing tumors portended to poorer prognosis. Given the fact that LKB1 mutant lung tumors are immune suppressed and respond poorly to immune checkpoint inhibitors, we hypothesize that TNKS potentially could be the negative regulator of LKB1 that induce immune suppression in LKB1 wild type tumors. We will test our hypothesis by: (1) determining the role of TNKS on conferring immunosuppression in the tumor microenvironment through the use of syngeneic orthotopic models and Genetically-Engineered Mouse Models (GEMMs) to better understand if TNKS levels confers immunosuppressive state in tumors; and (2) utilizing syngeneic orthotopic tumor models to evaluate the ability of TNKS expression to generate resistance to immunotherapy and determine the effectiveness of TNKS inhibition on enhancing immunotherapy response. Upon completion of this project, we will have a clearer understanding of the immunosuppressive state that is conferred by TNKS through the negative regulation of LKB1. This research will implicate TNKS as a target for clinical translation to improve current therapies in lung cancer.

项目摘要 肝激酶B1（LKB1）是细胞能量稳态和众所周知的肿瘤抑制剂的关键调节剂 在许多癌症中，尤其是肺癌，在大约30％的肿瘤中被删除的基因。 LKB1抑制 或耗竭会导致肿瘤发生，免疫抑制增加以及对 免疫检查点抑制剂。尽管LKB1负调节对肿瘤生长和 侵略性，没有已知的LKB1上游调节剂。通过理性设计的药物屏幕， 我们鉴定出坦克酶（TNKS; TNKS1，PARP5A和TNKS2或PARP5B），为上游负面负面 LKB1的监管机构。 TNK属于聚（ADP-核糖）聚合酶（PARP）紧密相关的成员 使用β-NAD+作为底物靶向蛋白质的ADP-核糖部分的家族称为阶层。 TNK对靶蛋白的荒原化通常会导致泛素化和蛋白酶体降解，例如 Axin（在Wnt信号传导中隔离APC/β-catenin），PTEN和端粒酶。然而，，荒原 LKB1不会导致LKB1降解，而是抑制LKB1活性。 TNK的过表达刺激肿瘤 细胞在体外增殖并增强lkb1依赖性的体内肿瘤发生。肺部肿瘤（两者 腺癌和鳞状细胞癌）表达肿瘤的LKB1中过表达TNKS1 定期预后较差。考虑到LKB1突变肺肿瘤免疫抑制，并且 对免疫检查点抑制剂的反应不佳，我们假设TNK可能是负面的 LKB1的调节剂会影响LKB1野生型肿瘤中的免疫抑制。我们将通过： （1）确定TNK在肿瘤微环境中通过 使用合成型原位模型和遗传工程的小鼠模型（GEMM）来更好地理解 如果TNK水平承认肿瘤中的免疫抑制状态； （2）利用合成原位肿瘤模型 评估TNK表达产生对免疫疗法的抗性的能力，并确定 TNK抑制对增强免疫疗法反应的有效性。该项目完成后，我们 将对TNK赋予的免疫抑制状态有更清晰的了解 LKB1的负调节。这项研究将牵涉到TNK作为临床翻译的目标以改进 当前的肺癌疗法。