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Regulation of anti-tumor immunity by HDAC11

HDAC11 调节抗肿瘤免疫

基本信息

批准号：
10524142
负责人：
Rong Li
金额：
$ 8.44万
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/10524142
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.

项目总结/文摘