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.

项目摘要/摘要免疫疗法领域的最新发展显然支持免疫系统的贡献在根除癌症中。组蛋白脱乙酰基酶（HDAC）抑制剂目前用于治疗许多恶性肿瘤和积累证据表明，HDAC抑制剂的许多抗癌作用涉及免疫系统。以前，关于HDAC11在免疫和癌症中的作用的信息有限。我们发现了 HDAC11负责调节抗原呈递细胞中的IL-10产生。我们还发现HDAC11是在T淋巴细胞和嗜中性粒细胞中高度表达，随后表明HDAC11中断T 细胞与增强的促炎细胞因子谱和效应分子产生有关。 t 缺乏HDAC11的细胞在体外不太容易受到调节T细胞抑制的影响，对耐受性难治性体内诱导并在移植的地幔细胞淋巴瘤鼠中显示出增强的抗肿瘤反应型号。此外，HDAC11是中性粒细胞的多方面调节剂。没有HDAC11 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的有效新颖活动，即去除长链脂肪来自蛋白质赖氨酸残基的酰基。这种新型活性比其脱乙酰基酶高10,000倍活动。使用合成小鼠对小鼠模型，我们在HDAC11 Wildtype和敲除（KO）小鼠。 HDAC11 KO小鼠中的合子淋巴瘤细胞的生长显着被抑制，指出HDAC11在肿瘤微环境中的关键作用。在此重新提交中应用的中心假设是HDAC11通过其缺陷酰化重编程抗癌免疫力活动并提出了潜在的癌症治疗药物靶标。我们的长期目标是对HDAC11在抗肿瘤中的作用有详细的分子理解免疫。这项工作的结果将：（1）更好地理解HDAC11的抗肿瘤行为；（2）扩展对癌症蛋白质赖氨酸缺乏酰化的功能理解；（3）发展更好的治疗通过靶向赖氨酸缺乏酰化机制来实现癌症的策略；（4）产生选择性 HDAC11抑制剂将加速新的癌症治疗策略。