ITIM-receptors for cancer treatment

用于癌症治疗的 ITIM 受体

• 批准号: 10561601
• 负责人: CHENGCHENG ZHANG
• 金额: $ 56.94万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561601
• 关键词: AIM2 gene; Antibodies; Biology; Blocking Antibodies; Cancer Patient; Cells; Cholecalciferol; Collaborations; Coupled; DNA; Development; Family; Genetic Transcription; Goals; Hormones; Human; ITIM; Immune; Immunology; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Inflammasome; Inositol; Leukocytes; Ligand Binding Domain; Malignant - descriptor; Malignant Neoplasms; Mediator; Membrane Glycoproteins; Modeling; Molecular; Monocytic leukemia; Mus; Myeloid-derived suppressor cells; Natural Immunity; PD-1/PD-L1; PD-L1 blockade; PTPN11 gene; PTPN6 gene; Phosphoric Monoester Hydrolases; Play; Proteins; Regulation; Role; Signal Transduction; Solid; Supporting Cell; Surface; T-Lymphocyte; Testing; Texas; Therapeutic; Up-Regulation; Vitamin D; cancer immunotherapy; cancer invasiveness; cancer therapy; cancer type; checkpoint receptors; chimeric antigen receptor T cells; extracellular; gain of function; immune checkpoint; in vivo; insight; leukemia; loss of function; member; migration; monocyte; mouse model; novel; novel strategies; novel therapeutic intervention; patient derived xenograft model; progenitor; receptor; recruit; sensor; stem cells; tumor; tumorigenic

Abstract T cell-centered immunotherapies, including PD-1/PD-L1 blockade, have been successful in treating some types of cancers but not others. The roles of other immune cells including immunosuppressive monocytic cells in tumor development and treatment are not well defined. A better understanding of the molecular regulation of signaling and function of these monocytic cells will support development of novel therapeutic strategies for cancer treatment. The leukocyte Ig-like receptor subfamily B (LILRB) proteins are a group of type I transmembrane glycoproteins with extracellular Ig-like domains that bind ligands and intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that can recruit tyrosine phosphatases SHP1, SHP2, or the inositol-phosphatase SHIP. We have been investigating the roles of this family of immune checkpoint receptors in tumor development. We demonstrated that several ITIM-receptors including LILRB2, LILRB4, and a related receptor LAIR1 support leukemia development. As the most restrictively expressed member of the LILRB family, LILRB4 is mainly expressed on monocytic cells but not on stem cells or progenitors. We and others further demonstrated that LILRB4 is a surface marker for monocytic AML and monocytic myeloid-derived suppressor cells. Importantly, we elucidated two novel functions of LILRB4: it supports infiltration of malignant monocytic cells and relieves immune inhibition of T cells. Furthermore, we developed anti-LILRB4 blocking antibodies and CAR-T cells that efficiently inhibit monocytic leukemia development in various mouse models including humanized and patient-derived xenografted mice. Here, based on new preliminary results, we propose the following Aims to test the hypothesis that the expression and signaling of LILRB4 in immunosuppressive monocytic cells support tumor development. In Aim 1, we will determine the function of LILRB4 signaling in immunosupressive monocytic cells and whether LILRB4 blocking/targeting inhibits tumor development. We will then determine how LILRB4 expression is transcriptionally regulated by extrinsic factors in Aim 2. Finally we will determine whether the DNA sensor protein Absent In Melanoma 2 (AIM2) is a key downstream effector of LILRB4 signaling in Aim 3. Our study will provide important mechanistic insights into immune checkpoint biology and directly guide the development of novel immunotherapies for cancer treatment.

摘要 以T细胞为中心的免疫疗法，包括PD-1/PD-L1阻断，已经取得了成功。 治疗某些类型的癌症，但不是其他人。其他免疫细胞的作用，包括 免疫抑制性单核细胞在肿瘤发展和治疗中的作用并不理想 定义了更好地理解信号传导的分子调控和 这些单核细胞将支持癌症新治疗策略的发展 治疗白细胞免疫球蛋白样受体亚家族B（LILRB）蛋白是一类 I具有结合配体的胞外Ig样结构域的跨膜糖蛋白， 基于酪氨酸的细胞内免疫受体抑制基序（ITIM）， 酪氨酸磷酸酶SHP 1、SHP 2或肌醇-磷酸酶SHIP。我们一直 研究这个免疫检查点受体家族在肿瘤中的作用 发展我们证明了几种ITIM受体，包括LILRB 2，LILRB 4， 和相关受体LAIR 1支持白血病的发展。作为最严格的 作为LILRB家族的表达成员，LILRB 4主要在单核细胞上表达 而不是干细胞或祖细胞。我们和其他人进一步证明了LILRB 4是 单核细胞AML和单核细胞髓源性抑制细胞的表面标志物。 重要的是，我们阐明了LILRB 4的两个新功能：它支持细胞渗透 恶性单核细胞并解除T细胞的免疫抑制。而且我们 开发了抗LILRB 4阻断抗体和CAR-T细胞， 单核细胞白血病在各种小鼠模型中的发展，包括人源化和 患者来源的异种移植小鼠。在这里，基于新的初步结果，我们提出了 以下目的是检验LILRB 4在人结肠癌中的表达和信号传导的假设。 免疫抑制性单核细胞支持肿瘤发展。在目标1中，我们 确定LILRB 4信号传导在免疫抑制性单核细胞中的功能， LILRB 4阻断/靶向是否抑制肿瘤发展。然后我们将决定 LILRB 4表达如何受目标2中的外在因子的转录调控。最后 我们将确定黑色素瘤2（AIM 2）中缺失的DNA传感器蛋白是否是一个关键， Aim 3中LILRB 4信号传导的下游效应子。我们的研究将提供重要的 对免疫检查点生物学的机械见解，并直接指导开发 癌症治疗的新型免疫疗法。