Understanding PD-L1/L2 protein regulation, detection and signaling to predict melanoma therapeutic sensitivity

了解 PD-L1/L2 蛋白调控、检测和信号传导以预测黑色素瘤治疗敏感性

基本信息

  • 批准号:
    10358524
  • 负责人:
  • 金额:
    $ 21.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-03-01 至 2023-02-28
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Modulators and effectors of anti-PD-1 responsiveness in cancer include T cell infiltration, an immune- suppressive microenvironment, tumor mutational burden, and tumor cell-intrinsic pathway (e.g., - catenin) alterations. Cell-surface PD-L1 level has been implicated as a baseline predictive marker of anti-PD-1 responsiveness, and cell-surface PD-L2 level may have predictive value independent of PD- L1. In melanoma, MAPK inhibitor therapy strongly induces PD-L1/L2 expression levels in tumor, stromal and immune cells, suggesting contributions to adaptive resistance. Induction of cell-surface PD-L1 is central to adaptive immune resistance and implicated as a mechanism of acquired anti-PD-1 resistance. Moreover, the regulation of surface PD-L1 protein stability has been implicated in tumor immune surveillance, where increased degradation augments tumor-specific T cell activity. We hypothesize that a better understanding of regulatory mechanisms controlling cell-surface PD- L1/L2 stability, clinical detection, and tumor cell-intrinsic pro-survival signaling could shed insights into melanoma immune evasion and therapeutic responsiveness. We will use proteomic approaches to dissect these processes and to explore the melanoma surface glycoproteome, the PD-L1/L2 interactome and the cytoplasmic signalosome in order to nominate mechanisms and/or markers of therapeutic responsiveness. We will interrogate iteratively clinical tumor samples and syngeneic mouse models of Braf, Nras and Nf1 mutant melanoma. These immune-competent models of melanoma are clinically relevant given their UV-induced high mutational burdens, dependence on CD8 T cells for therapeutic responses and capability for widespread metastases, including metastases to the brain. We will use cell-surface labeling of sialic acid-containing glycans to analyze the live cell surface glycoproteome, co-immunoprecipitation of PD-L1/L2 to enrich for interactomes, and APEX-based proteomic strategy to define in situ dynamic intracellular PD-L1/L2 neighborhood interactomes in response to PD-1 ligation or IFN treatment. We will address what regulate PD-L1/L2 ubiquitination, recycling and degradation, how glycosylation affects membrane PD-L1 immunohistochemical detection, whether deglycosylation improves prediction of anti-PD-1 responses at baseline and on- treatment, and how novel cytoplasmic motifs of PD-L1/L2 mediate PD-1-dependent tumor cell pro- survival signaling. Using proximity ligation assays on clinical melanoma, we will test whether PD-L1/L2 tumor cell-intrinsic signaling reduces therapy efficacy. These proteomic approaches should advance our understanding of therapy response patterns in metastatic melanoma and nominate predictive biomarkers and combinatorial targets.
项目总结/摘要 癌症中抗PD-1反应性的调节剂和效应物包括T细胞浸润、免疫调节剂和免疫调节剂。 抑制性微环境、肿瘤突变负荷和肿瘤细胞内在途径(例如,- 连环蛋白)改变。细胞表面PD-L1水平被认为是一种基线预测标志物, 抗PD-1反应性和细胞表面PD-L2水平可能具有独立于PD-1的预测价值。 L1。在黑色素瘤中,MAPK抑制剂治疗强烈诱导肿瘤中的PD-L1/L2表达水平, 基质和免疫细胞,这表明适应性抗性的贡献。细胞表面诱导 PD-L1是获得性免疫抵抗的核心,并涉及获得性抗PD-1的机制 阻力此外,表面PD-L1蛋白稳定性的调节与肿瘤的发生有关。 免疫监视,其中增加的降解增强肿瘤特异性T细胞活性。 我们假设,更好地了解控制细胞表面PD的调节机制, L1/L2稳定性、临床检测和肿瘤细胞内在的促生存信号传导可以揭示 黑色素瘤免疫逃避和治疗反应性。我们将使用蛋白质组学方法, 剖析这些过程,并探索黑色素瘤表面糖蛋白组,PD-L1/L2 相互作用体和细胞质信号体,以命名的机制和/或标志物, 治疗反应我们将反复询问临床肿瘤样品和同基因小鼠 Braf、Nras和Nf 1突变型黑色素瘤模型。这些免疫活性的黑色素瘤模型是 考虑到其UV诱导的高突变负荷, 治疗反应和广泛转移(包括脑转移)的能力。 我们将使用细胞表面标记含唾液酸的聚糖来分析活细胞表面 糖蛋白组,PD-L1/L2的共免疫沉淀以富集相互作用组,以及基于APEX的 蛋白质组学策略,以确定原位动态细胞内PD-L1/L2邻近相互作用组, 对PD-1连接或IFN γ治疗的应答。我们将讨论是什么调节PD-L1/L2泛素化, 回收和降解,糖基化如何影响膜PD-L1免疫组化 检测,去糖基化是否改善了基线和治疗期间抗PD-1应答的预测。 治疗,以及PD-L1/L2的新型胞质基序如何介导PD-1依赖性肿瘤细胞前体, 生存信号我们将在临床黑色素瘤上使用邻位连接试验,检测PD-L1/L2 肿瘤细胞内在信号传导降低治疗功效。这些蛋白质组学方法应该会有所进展 我们对转移性黑色素瘤治疗反应模式的理解和提名的预测 生物标志物和组合靶标。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Multi-organ landscape of therapy-resistant melanoma.
  • DOI:
    10.1038/s41591-023-02304-9
  • 发表时间:
    2023-05
  • 期刊:
  • 影响因子:
    82.9
  • 作者:
    Liu, Sixue;Dharanipragada, Prashanthi;Lomeli, Shirley H.;Wang, Yan;Zhang, Xiao;Yang, Zhentao;Lim, Raymond J.;Dumitras, Camelia;Scumpia, Philip O.;Dubinett, Steve M.;Moriceau, Gatien;Johnson, Douglas B.;Moschos, Stergios J.;Lo, Roger S.
  • 通讯作者:
    Lo, Roger S.
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

ROGER S LO其他文献

ROGER S LO的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('ROGER S LO', 18)}}的其他基金

Core 1: Mouse Model and Tissue Biobank Core
核心 1:小鼠模型和组织生物库核心
  • 批准号:
    10526106
  • 财政年份:
    2022
  • 资助金额:
    $ 21.44万
  • 项目类别:
Core 1: Mouse Model and Tissue Biobank Core
核心 1:小鼠模型和组织生物库核心
  • 批准号:
    10708931
  • 财政年份:
    2022
  • 资助金额:
    $ 21.44万
  • 项目类别:
Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma
项目 1:增强 MEK 抑制剂对 MUTNRAS 黑色素瘤疗效的策略
  • 批准号:
    10261396
  • 财政年份:
    2020
  • 资助金额:
    $ 21.44万
  • 项目类别:
Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma
项目 1:增强 MEK 抑制剂对 MUTNRAS 黑色素瘤疗效的策略
  • 批准号:
    10443859
  • 财政年份:
    2020
  • 资助金额:
    $ 21.44万
  • 项目类别:
Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma
项目 1:增强 MEK 抑制剂对 MUTNRAS 黑色素瘤疗效的策略
  • 批准号:
    10025136
  • 财政年份:
    2020
  • 资助金额:
    $ 21.44万
  • 项目类别:
Combinatorial Targeting of Epigenomic and Microenvironmental Pathways to Suppress MAPK Inhibitor Resistance in Melanoma
表观基因组和微环境途径的组合靶向抑制黑色素瘤中 MAPK 抑制剂耐药性
  • 批准号:
    10439777
  • 财政年份:
    2013
  • 资助金额:
    $ 21.44万
  • 项目类别:
Combinatorial Targeting of Epigenomic and Microenvironmental Pathways to Suppress MAPK Inhibitor Resistance in Melanoma
表观基因组和微环境途径的组合靶向抑制黑色素瘤中 MAPK 抑制剂耐药性
  • 批准号:
    10189526
  • 财政年份:
    2013
  • 资助金额:
    $ 21.44万
  • 项目类别:
Overcoming acute, adaptive BRAF inhibitor resistance in melanoma
克服黑色素瘤中急性、适应性 BRAF 抑制剂耐药性
  • 批准号:
    8595186
  • 财政年份:
    2013
  • 资助金额:
    $ 21.44万
  • 项目类别:
Combinatorial Targeting of Epigenomic and Microenvironmental Pathways to Suppress MAPK Inhibitor Resistance in Melanoma
表观基因组和微环境途径的组合靶向抑制黑色素瘤中 MAPK 抑制剂耐药性
  • 批准号:
    9912727
  • 财政年份:
    2013
  • 资助金额:
    $ 21.44万
  • 项目类别:
Overcoming acute, adaptive BRAF inhibitor resistance in melanoma
克服黑色素瘤中急性、适应性 BRAF 抑制剂耐药性
  • 批准号:
    9283342
  • 财政年份:
    2013
  • 资助金额:
    $ 21.44万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 21.44万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 21.44万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 21.44万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 21.44万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 21.44万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 21.44万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 21.44万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 21.44万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 21.44万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 21.44万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了