ITIM-receptors for cancer treatment

用于癌症治疗的 ITIM 受体

• 批准号: 10360629
• 负责人: CHENGCHENG ZHANG
• 金额: $ 56.56万
• 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/10360629
• 关键词: AIM2 gene; Antibodies; Biology; Blocking Antibodies; Cancer Patient; Cells; Cholecalciferol; Collaborations; Coupled; DNA; Development; Family; Genetic Transcription; Glycoproteins; Goals; Hormones; Human; ITIM; Immune; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Inflammasome; Inositol; Institutes; Lead; Leukocytes; Ligand Binding Domain; Malignant - descriptor; Malignant Neoplasms; Mediator of activation protein; 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; base; 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; tumor immunology

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，已经取得成功 用于治疗某些类型的癌症，而不是其他类型的癌症。其他免疫细胞的作用包括 免疫抑制单核细胞在肿瘤发生和治疗中的作用 已定义。更好地理解信号转导的分子调控和功能 这些单核细胞将支持癌症新治疗策略的开发 治疗。白细胞Ig样受体B亚家族(LILRB)蛋白是一组 具有细胞外Ig样结构域的跨膜糖蛋白结合配体和 细胞内免疫受体酪氨酸抑制基序(ITIMs)可招募 酪氨酸磷酸酶SHP1、SHP2或肌醇磷酸酶SHIP。我们一直在 研究这一免疫检查点受体家族在肿瘤中的作用 发展。我们证实了几种ITIM受体，包括LilrB2，LILRB4， 一个相关的受体LAIR1支持白血病的发生。作为最具限制性的 LILRB4是LILRB家族成员，主要在单核细胞上表达 但不是在干细胞或祖细胞上。我们和其他人进一步证明了LILRB4是 单核细胞急性髓系白血病和单核细胞髓系来源的抑制细胞的表面标记。 重要的是，我们阐明了LILRB4的两个新功能：它支持 抑制恶性单核细胞，解除T细胞的免疫抑制作用。此外，我们 开发出抗LILRB4封闭抗体和CAR-T细胞，有效抑制 单核细胞白血病在不同小鼠模型中的发展 患者来源的异种移植小鼠。在此，基于新的初步结果，我们提出了 下面的目的是验证LILRB4的表达和信号转导在 免疫抑制的单核细胞支持肿瘤的发展。在目标1中，我们将 确定LILRB4信号在免疫抑制单核细胞中的功能 LILRB4阻断/靶向是否抑制肿瘤的发展。然后我们将确定 在Aim 2中，LILRB4的表达是如何被外源因子转录调控的。 我们将确定黑色素瘤2中缺失的DNA传感器蛋白(AIM2)是否是关键 LILRB4信号在AIM 3中的下游效应。我们的研究将为 对免疫检查点生物学的机械性见解并直接指导开发 用于癌症治疗的新型免疫疗法。