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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：
ROGER S LO
金额：
$ 21.44万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
https://reporter.nih.gov/project-details/10358524
关键词：
Address Affect Affinity Affinity Chromatography Animal Model Antigen Presentation Apoptotic Archives Area Binding Biological Biological Assay Biotin Brain CD8-Positive T-Lymphocytes CD80 gene CD8B1 gene Cancer cell line Cell Surface Proteins Cell surface Cells Clinical Co-Immunoprecipitations Cues Cytoplasmic Tail Cytotoxic T-Lymphocytes Dependence Detection Down-Regulation Drug resistance Excision Genetic Genomics Growth Heterogeneity Immune Immune Evasion Immunocompetent Immunologic Surveillance Immunologics Immunotherapeutic agent Immunotherapy In Situ Interferons Knowledge Label Ligation Link MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Melanoma Cell Membrane Membrane Lipids Metastatic Melanoma Metastatic malignant neoplasm to brain Mission Mitogen-Activated Protein Kinase Inhibitor Modeling Mutation NF1 gene Neighborhoods Neoplasm Metastasis Organ PD-1 blockade PD-1/PD-L1 Pathway interactions Patients Pattern Polysaccharides Predictive Value Process Proteins Proteome Proteomics Public Health Radial Recycling Regulation Resistance Sampling Shotguns Sialic Acids Signal Transduction Surface T-Lymphocyte Techniques Testing Therapeutic Tissues Treatment Efficacy Tumor Immunity Tumor Tissue Tumor-Derived Tumor-infiltrating immune cells UV induced Ubiquitination anti-PD-1 anti-PD1 therapy antibody detection anticancer research base cancer therapy clinically relevant combinatorial design feasibility testing glycosylation immune checkpoint immune resistance improved in vivo individualized medicine inhibitor therapy insight melanoma mouse model mutant neoplastic cell non-genetic novel novel therapeutic intervention optimal treatments pre-clinical predict clinical outcome predictive marker programmed cell death ligand 1 programmed cell death protein 1 response stem targeted treatment therapeutic biomarker therapy outcome therapy resistant tissue archive transcriptomics translational study treatment response tumor ubiquitin-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.

项目摘要/摘要肿瘤中抗PD-1反应性的调节器和效应器包括T细胞渗透，一种免疫- 抑制性微环境、肿瘤突变负荷和肿瘤细胞内在途径(如- 连环蛋白)改变。细胞表面PD-L1水平已被认为是一种基线预测标志抗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PD-L1/L2的表达水平，基质细胞和免疫细胞，提示对适应性抵抗有贡献。细胞表面的诱导 PD-L1是获得性免疫抵抗的中心，是获得性抗PD-1的机制之一抵抗。此外，表面PD-L1蛋白稳定性的调节也与肿瘤有关免疫监测，其中降解增加增强肿瘤特异性T细胞活性。我们假设，更好地理解控制细胞表面PD的调控机制- L1/L2的稳定性、临床检测和肿瘤细胞固有的促生存信号可以揭示黑色素瘤免疫逃避和治疗反应。我们将使用蛋白质组学方法解剖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小体，以提名机制和/或标记治疗反应性。我们将反复询问临床肿瘤样本和同基因小鼠 BRAF、NRAS和NF1突变型黑色素瘤模型。黑色素瘤的这些免疫活性模型是考虑到其紫外线诱导的高突变负荷，临床上对CD8 T细胞的依赖对广泛转移的治疗反应和能力，包括脑转移。我们将使用含唾液酸聚糖的细胞表面标记来分析活细胞表面糖蛋白质组，PD-L1/L2免疫共沉淀富集相互作用，以及基于APEX的用蛋白质组学方法原位确定细胞内动态PD-L1/L2邻域相互作用对PD-1结扎或干扰素治疗的反应。我们将讨论调节PD-L1/L2泛素化的因素，循环和降解，糖基化如何影响膜PD-L1免疫组织化学检测去糖基化是否改善基线和On-1的抗PD-1反应的预测新的PD-L1/L2胞浆基序如何介导PD-1依赖的肿瘤细胞生存信号。通过对临床黑色素瘤的邻近结扎试验，我们将检测PD-L1/L2 肿瘤细胞固有的信号转导降低了治疗效果。这些蛋白质组学方法应该会取得进展我们对转移性黑色素瘤治疗反应模式的理解和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：
NATURE MEDICINE
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.