Regulation of anti-tumor immunity by HDAC11

HDAC11 调节抗肿瘤免疫

基本信息

批准号：
10436938
负责人：
Rong Li
金额：
$ 56.97万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10436938
关键词：
Acylation Antigen-Presenting Cells Antitumor Response B lymphoid malignancy Cancer Model Cause of Death Cell Cycle Cell Line Cell Polarity Cell physiology Cells Chemicals Collaborations Complex Data Deacetylase Deacetylation Development Disease Enzyme Inhibitor Drugs Excision Family Functional disorder Genetic Models Glycine Hydroxymethyltransferase Goals Growth HDAC11 gene Healthcare Hematologic Neoplasms Hematopoietic Neoplasms Histone Deacetylase Histone Deacetylase Inhibitor Human IFNAR1 gene Immune Immune response Immune signaling Immune system Immunity Immunotherapy In Vitro Individual Infiltration Inflammatory Interferon Type I Interferons Interleukin-10 Knock-out Knockout Mice Knowledge Laboratories Lymphoid Tissue Lymphoma Lymphoma cell Lysine Malignant Neoplasms Mantle Cell Lymphoma Mediating Mediator of activation protein Mission Modeling Molecular Monomeric GTP-Binding Proteins Mus Non-Hodgkin&apos s Lymphoma Patients Phagocytes Pharmacology Pharmacotherapy Physiological Play Positioning Attribute Process Production Property Proteins Refractory Regulation Regulatory T-Lymphocyte Research Research Personnel Role Signal Transduction Site T-Lymphocyte Testing Therapeutic Therapeutic Effect Transplantation Tumor Immunity Tumor-infiltrating immune cells United States Universities Washington Wild Type Mouse Work acyl group anti-cancer anti-tumor immune response base cancer therapy cdc42 GTP-Binding Protein cell motility cytokine fatty acylation immune function immunoregulation improved in vivo inhibitor insight isopeptidase lymph nodes migration mouse model multidisciplinary neutrophil new therapeutic target novel novel drug class novel therapeutics pharmacokinetics and pharmacodynamics protein function rho tool treatment strategy tumor tumor behavior tumor growth tumor microenvironment tumorigenesis tumorigenic

项目摘要

Project Summary/Abstract Recent developments in the field of immunotherapy clearly support the contribution of the immune system in eradicating cancer. Histone deacetylase (HDAC) inhibitors are currently employed in the treatment of many malignancies, and accumulating evidence suggests that many of the anticancer effects of HDAC inhibitors involve the immune system. Previously, there was limited information on the role of HDAC11 in immunity and cancer. We discovered that HDAC11 negatively regulates IL-10 production in antigen-presenting cells. We also found that HDAC11 is highly expressed in T lymphocytes and neutrophils and, subsequently, revealed that HDAC11 disruption in T cells is associated with an enhanced pro-inflammatory cytokine profile and effector molecule production. T cells lacking HDAC11 are less susceptible to regulatory T cell suppression in vitro, are refractory to tolerance induction in vivo, and display enhanced anti-tumor responses in transplanted mantle cell lymphoma murine models. Furthermore, HDAC11 is a multifaceted regulator of neutrophils. The absence of Hdac11 in neutrophils significantly increases cellular production of proinflammatory cytokines and promotes cell migration and phagocytic capacity. More recently, our group discovered an efficient novel activity for HDAC11, the removal of long-chain fatty acyl groups from protein lysine residues. This novel activity is >10,000-fold more efficient than its deacetylase activity. Using a syngeneic mouse-to-mouse model, we established ectopic tumors in Hdac11 wildtype and knockout (KO) mice. The growth of the syngeneic lymphoma cells in the Hdac11 KO mice was markedly inhibited, pointing toward a crucial role of HDAC11 in the tumor microenvironment. In this resubmission application, the central hypothesis is that HDAC11 reprograms anti-cancer immunity via its defatty-acylation activity and presents a potential novel drug target for cancer treatment. Our long-term goal is to develop a detailed molecular understanding of HDAC11's role in anti-tumor immunity. Results from this work will: (1) provide a better understanding of the anti-tumor behavior of HDAC11; (2) expand a functional understanding of protein lysine defatty-acylation in cancer; (3) develop better treatment strategies for cancer through targeting the lysine defatty-acylation mechanism; and (4) produce selective HDAC11 inhibitors, which will accelerate the development of new cancer treatment strategies.

项目概要/摘要免疫治疗领域的最新发展明确支持免疫系统的贡献在根除癌症方面。组蛋白脱乙酰酶 (HDAC) 抑制剂目前用于治疗许多疾病恶性肿瘤，并且越来越多的证据表明 HDAC 抑制剂的许多抗癌作用涉及免疫系统。此前，关于 HDAC11 在免疫和癌症中的作用的信息有限。我们发现 HDAC11 负向调节抗原呈递细胞中 IL-10 的产生。我们还发现 HDAC11 在 T 淋巴细胞和中性粒细胞中高度表达，随后揭示了 T 细胞中 HDAC11 的破坏细胞与增强的促炎细胞因子谱和效应分子产生相关。时间缺乏 HDAC11 的细胞在体外不易受到调节性 T 细胞抑制的影响，难以耐受体内诱导，并在移植的套细胞淋巴瘤小鼠中表现出增强的抗肿瘤反应模型。此外，HDAC11 是中性粒细胞的多方面调节剂。 Hdac11 的缺失中性粒细胞显着增加促炎细胞因子的细胞产生并促进细胞迁移和吞噬能力。最近，我们的小组发现了 HDAC11 的一种有效的新活性，即去除长链脂肪来自蛋白质赖氨酸残基的酰基。这种新颖的活性比其脱乙酰酶效率高 10,000 倍以上活动。使用同基因小鼠对小鼠模型，我们在 Hdac11 野生型和 Hdac11 野生型中建立了异位肿瘤。基因敲除（KO）小鼠。 Hdac11 KO小鼠同基因淋巴瘤细胞生长显着抑制，表明 HDAC11 在肿瘤微环境中发挥着至关重要的作用。在这次重新提交中应用中，中心假设是 HDAC11 通过其脱脂酰化重新编程抗癌免疫活性并为癌症治疗提供了潜在的新药物靶点。我们的长期目标是对 HDAC11 的抗肿瘤作用产生详细的分子理解免疫。这项工作的结果将：（1）更好地了解 HDAC11 的抗肿瘤行为； (2) 扩大对癌症中蛋白质赖氨酸脱脂酰化的功能理解； (3)开发更好的治疗方法通过针对赖氨酸脱脂酰化机制的癌症策略； (4) 产生选择性的 HDAC11抑制剂，这将加速新的癌症治疗策略的开发。