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
- 来源:
- 关键词:AddressAffectAffinityAffinity ChromatographyAnimal ModelAntigen PresentationApoptoticArchivesAreaBindingBiologicalBiological AssayBiotinBrainCD8-Positive T-LymphocytesCD80 geneCD8B1 geneCancer cell lineCell Surface ProteinsCell surfaceCellsClinicalCo-ImmunoprecipitationsCuesCytoplasmic TailCytotoxic T-LymphocytesDependenceDetectionDown-RegulationDrug resistanceExcisionGeneticGenomicsGrowthHeterogeneityImmuneImmune EvasionImmunocompetentImmunologic SurveillanceImmunologicsImmunotherapeutic agentImmunotherapyIn SituInterferonsKnowledgeLabelLigationLinkMAP Kinase GeneMalignant NeoplasmsMalignant neoplasm of lungMass Spectrum AnalysisMediatingMelanoma CellMembraneMembrane LipidsMetastatic MelanomaMetastatic malignant neoplasm to brainMissionMitogen-Activated Protein Kinase InhibitorModelingMutationNF1 geneNeighborhoodsNeoplasm MetastasisOrganPD-1 blockadePD-1/PD-L1Pathway interactionsPatientsPatternPolysaccharidesPredictive ValueProcessProteinsProteomeProteomicsPublic HealthRadialRecyclingRegulationResistanceSamplingShotgunsSialic AcidsSignal TransductionSurfaceT-LymphocyteTechniquesTestingTherapeuticTissuesTreatment EfficacyTumor ImmunityTumor TissueTumor-DerivedTumor-infiltrating immune cellsUV inducedUbiquitinationanti-PD-1anti-PD1 therapyantibody detectionanticancer researchbasecancer therapyclinically relevantcombinatorialdesignfeasibility testingglycosylationimmune checkpointimmune resistanceimprovedin vivoindividualized medicineinhibitor therapyinsightmelanomamouse modelmutantneoplastic cellnon-geneticnovelnovel therapeutic interventionoptimal treatmentspre-clinicalpredict clinical outcomepredictive markerprogrammed cell death ligand 1programmed cell death protein 1responsestemtargeted treatmenttherapeutic biomarkertherapy outcometherapy resistanttissue archivetranscriptomicstranslational studytreatment responsetumorubiquitin-protein ligase
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.
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ROGER S LO其他文献
ROGER S LO的其他文献
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{{ 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:
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:
8595186 - 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:
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