Regulation of anti-tumor immunity by HDAC11

HDAC11 调节抗肿瘤免疫

• 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
• 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' 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

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.

项目总结/摘要 免疫治疗领域的最新进展清楚地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癌症。 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。 以前，关于HDAC 11在免疫和癌症中的作用的信息有限。我们发现 HDAC 11负调节抗原呈递细胞中IL-10的产生。我们还发现HDAC 11是 HDAC 11在T淋巴细胞和中性粒细胞中高度表达，随后揭示了HDAC 11在T淋巴细胞中破坏， 细胞与增强的促炎细胞因子谱和效应分子产生相关。不 缺乏HDAC 11的细胞在体外对调节性T细胞抑制较不敏感， 体内诱导，并在移植套细胞淋巴瘤小鼠中显示增强的抗肿瘤应答 模型此外，HDAC 11是中性粒细胞的多方面调节剂。Hdac 11的缺失 中性粒细胞显著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，我们的研究小组发现了HDAC 11的一种有效的新活性，即去除长链脂肪酸。 来自蛋白质赖氨酸残基的酰基。这种新的活性比其脱乙酰酶的效率高10，000倍以上 活动使用同基因小鼠-小鼠模型，我们在Hdac 11野生型和Hdac 12中建立了异位肿瘤。 敲除（KO）小鼠。Hdac 11基因敲除小鼠体内同基因淋巴瘤细胞的生长明显受到抑制， 抑制，指向HDAC 11在肿瘤微环境中的关键作用。在这次重新提交的 应用中，中心假设是HDAC 11通过其脱乙酰化重新编程抗癌免疫 活性，并提出了一个潜在的新的药物靶点，用于癌症治疗。 我们的长期目标是对HDAC 11在抗肿瘤中的作用进行详细的分子理解。 免疫力本研究的结果将：（1）为进一步了解HDAC 11的抗肿瘤作用提供理论依据; (2)扩大对蛋白质赖氨酸脱乙酰化在癌症中的功能性理解;（3）开发更好的治疗方法 通过靶向赖氨酸脱乙酰化机制治疗癌症的策略;以及（4）产生选择性的 HDAC 11抑制剂，这将加速新的癌症治疗策略的发展。