Reprogramming myeloid cells to inhibit cancer development
重新编程骨髓细胞以抑制癌症发展
基本信息
- 批准号:10687107
- 负责人:
- 金额:$ 36.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-22 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinBindingBinding ProteinsBiological AssayBiologyBlocking AntibodiesBreast Cancer PatientCell Fate ControlCell ReprogrammingDataDevelopmentExtracellular ProteinFamilyFamily memberGalectin 4GoalsHumanHuman ActivitiesITIMImmuneImmune responseImmunosuppressionIn VitroInositolLeukocytesLigand BindingLigandsMalignant NeoplasmsMapsMediatingMembrane GlycoproteinsMolecularMusMyelogenousMyeloid CellsMyeloid-derived suppressor cellsPTPN6 genePathway interactionsPhase I Clinical TrialsPhosphoric Monoester HydrolasesPopulationPrimatesProtein Tyrosine PhosphataseProteinsRegulationReporterResearchRoleSTAT3 geneSignal PathwaySignal TransductionSolidSupporting CellTRAF2 geneTestingTransgenic MiceTransgenic OrganismsUp-RegulationXenograft procedureanti-canceranti-cancer therapeuticcancer immunotherapeuticscancer therapycheckpoint receptorsextracellularhumanized mouseimmune checkpointimmunoregulationinhibiting antibodyinhibitorinnovationleukemia treatmentmembermouse modelmyeloid leukemia cellnovelnovel therapeutic interventionreceptorreceptor bindingrecruittumortumor microenvironment
项目摘要
Immunosuppressive myeloid cells including myeloid-derived suppressor cells (MDSCs)
contribute to multiple steps of cancer development. A better understanding of the
molecular regulation of the functions of these myeloid cells and the signaling pathways
will support development of novel anti-cancer therapeutic strategies. The leukocyte Ig-like
receptor subfamily B (LILRB) proteins are a group of immune inhibitory receptors with
intracellular immunoreceptor tyrosine-based inhibitory motifs. We have been studying the
roles of these receptors in cancer development and immune regulation. The studies by us
and others suggest that the LILRB family is becoming the next wave of myeloid immune
checkpoint targets for cancer treatment. Here we demonstrated that LILRB3, a myeloid-
specific member of this family, is functionally expressed on human MDSCs, and supports
cancer development in mouse models. Importantly, we identified galectin-4 as an
extracellular protein that binds to LILRB3 and induces LILRB3 activation, and the
intracellular domain of LILRB3 interacts with the adaptor protein TRAF2 to contribute to
NFκB upregulation. Furthermore, we developed anti-LILRB3 blocking antibodies that
efficiently inhibit immunosuppressive activity of human MDSCs in vitro and cancer
development in xenografted humanized mice and in LILRB3-transgenic mice. Our study
suggests that LILRB3 represents an attractive novel target for cancer treatment. Based
on new preliminary results, we propose the following Aims to test the hypothesis that
LILRB3-initiated signaling in immunosuppressive myeloid cells supports cancer
development. In Aim 1, we will determine the function of LILRB3 expressed on myeloid
cells in cancer development. We will then determine whether galectin-4 regulates LILRB3-
mediated signaling in tumor microenvironment to support cancer development in Aim 2.
Finally we will dissect LILRB3 signaling in immunosuppressive myeloid cells in Aim 3. Our
study will elucidate the molecular mechanisms by which LILRB3 regulates the activity of
immunosuppressive myeloid cells, and lead to the development of innovative anti-cancer
strategies based on targeting LILRB3 signaling.
免疫抑制性骨髓细胞,包括骨髓源性抑制细胞(MDSC)
导致癌症发展的多个步骤。更好地理解
这些髓样细胞功能的分子调控和信号通路
将支持开发新的抗癌治疗策略。白细胞Ig样
受体亚家族B(LILRB)蛋白是一组免疫抑制受体,
基于酪氨酸的细胞内免疫受体抑制基序。我们一直在研究
这些受体在癌症发展和免疫调节中的作用。我们的研究
其他研究表明,LILRB家族正在成为下一波骨髓免疫反应,
癌症治疗的检查点目标。在这里,我们证明了LILRB 3,一种骨髓-
该家族的特定成员,在人MDSC上功能性表达,并支持
小鼠模型中的癌症发展。重要的是,我们鉴定出半乳糖凝集素-4是一种
结合LILRB 3并诱导LILRB 3活化的细胞外蛋白,以及
LILRB 3的胞内结构域与衔接蛋白TRAF 2相互作用,
NFκB上调。此外,我们开发了抗LILRB 3阻断抗体,
有效抑制体外人MDSC的免疫抑制活性和癌症
在异种移植人源化小鼠和LILRB 3转基因小鼠中的发育。我们的研究
表明LILRB 3代表了一种有吸引力的癌症治疗新靶点。基于
根据新的初步结果,我们提出以下目标来检验假设,
LILRB 3在免疫抑制性骨髓细胞中引发的信号传导支持癌症
发展在目的1中,我们将确定LILRB 3在髓样细胞上表达的功能。
癌细胞的发展。然后,我们将确定半乳糖凝集素-4是否调节LILRB 3,
介导的信号传导,以支持Aim 2中的癌症发展。
最后,我们将在Aim 3中剖析免疫抑制性骨髓细胞中的LILRB 3信号传导。我们
这项研究将阐明LILRB 3调节细胞活性的分子机制。
免疫抑制骨髓细胞,并导致创新抗癌的发展
基于靶向LILRB 3信号传导的策略。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Fc gamma receptors promote antibody-induced LILRB4 internalization and immune regulation of monocytic AML.
- DOI:10.1093/abt/tbad025
- 发表时间:2024-01
- 期刊:
- 影响因子:0
- 作者:Morse, Joshua W;Gui, Xun;Deng, Mi;Huang, Ryan;Ye, Xiaohua;Zhao, Peng;Fan, Xuejun;Xiong, Wei;Zhang, Chengcheng;Zhang, Ningyan;An, Zhiqiang
- 通讯作者:An, Zhiqiang
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CHENGCHENG ZHANG其他文献
CHENGCHENG ZHANG的其他文献
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{{ truncateString('CHENGCHENG ZHANG', 18)}}的其他基金
The role of inhibitory receptors in leukemia development
抑制性受体在白血病发展中的作用
- 批准号:
9001318 - 财政年份:2013
- 资助金额:
$ 36.62万 - 项目类别:
The role of inhibitory receptors in leukemia development
抑制性受体在白血病发展中的作用
- 批准号:
8419564 - 财政年份:2013
- 资助金额:
$ 36.62万 - 项目类别:
The role of inhibitory receptors in leukemia development
抑制性受体在白血病发展中的作用
- 批准号:
8792836 - 财政年份:2013
- 资助金额:
$ 36.62万 - 项目类别:
The role of inhibitory receptors in leukemia development
抑制性受体在白血病发展中的作用
- 批准号:
9207741 - 财政年份:2013
- 资助金额:
$ 36.62万 - 项目类别:
Expansion of hematopoietic stem cells by Angiopoietin-like 2
通过血管生成素样 2 扩增造血干细胞
- 批准号:
7340625 - 财政年份:2006
- 资助金额:
$ 36.62万 - 项目类别:
Expansion of hematopoietic stem cells by Angiopoietin-like 2
通过血管生成素样 2 扩增造血干细胞
- 批准号:
7844803 - 财政年份:2006
- 资助金额:
$ 36.62万 - 项目类别:
Expansion of hematopoietic stem cells by Angiopoietin-like 2
通过血管生成素样 2 扩增造血干细胞
- 批准号:
7076781 - 财政年份:2006
- 资助金额:
$ 36.62万 - 项目类别:
Expansion of hematopoietic stem cells by Angiopoietin-like 2
通过血管生成素样 2 扩增造血干细胞
- 批准号:
7254070 - 财政年份:2006
- 资助金额:
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