The role of tumor cell-of-origin-specific PDL1 on tumorigenesis and tumor progression

肿瘤细胞源特异性PDL1在肿瘤发生和进展中的作用

基本信息

项目摘要

ABSTRACT This F31-diversity proposal investigates the role of PDL1 in early melanoma progression using our novel cancer cell-of-origin autochthonous mouse model. Our overarching hypothesis is that tumor-intrinsic PDL1 signals promote early tumor progression by both immune and non-immune mechanisms. Our proposal will define novel cell-intrinsic PDL1 signals in the melanoma cell-of-origin and established melanomas providing the first model distinguishing bona-fide biologic tumor-intrinsic PDL1 signaling in the absence of potentially confounding mechanisms due to genetic PDL1KO of a previously PDL1-replete tumor cell. We will address this hypothesis with the following aims: Aim 1 Test the hypothesis that melanocyte-intrinsic PDL1 signals promote early melanoma progression and treatment sensitivities. We will investigate melanocyte-intrinsic PDL1 signals, downstream effectors, and contributions of UV exposure facilitating early tumor progression using the PDL1KO TNQ61R mouse model we created, and littermate controls, in which PDL1 is specifically deleted in melanocytes. Transcriptomic (RNA-seq) and proteomic (Luminex, RPPA) dynamics will be assessed as melanocytes progress from PDL1-null benign nevi to malignant melanomas defining when PDL1 emerges during carcinogenesis and determining the genetic and proteomic milieu governing PDL1 expression in vivo and in vitro and its consequences. PDL1 regulation of oncogenic signals (e.g., NRAS, BRAF, MEK, ERK, mTORC1) will be tested using small molecule inhibitors and in vitro CRISPR replacement of mutant NrasQ61R for WT Nras or BRAFV600E. PDL1 suppression of immunogenic STING signals following skin UV exposure will be explored in parallel and as immunogenicity mechanisms are defined, their contributions to de novo tumor growth and treatment sensitivities will be tested in Aim 2. Aim 2 Define TME factors in melanocyte-intrinsic PDL1-drive progression and treatment vulnerabilities. We will test melanocyte PDL1-dependent TME immune dynamics using our PDL1KO TNQ61R model by harvesting non-malignant skin and induced tumor over time, assessing immune populations as tumors progress with flow cytometry. Immunoblots, Luminex, and qRT-PCR will test immunogenic STING signals and chemokine production ex vivo and immune cell co-localization with tumor will be assessed by confocal imaging. Alternative immunogenic pathways known to affect treatment efficacy (e.g., pyroptosis, RIG-I/MAVS) will be studied in similar fashion. Studies of PDL1KO TNQ61R mice and derived cell lines with ICB, immune cell depletion, and immune deficient mice test PDL1-driven immune-dependent targetable treatment vulnerabilities. Immune outcomes of PDL1/Nras cross talk will be defined complementary to signaling studies in Aim 1.
摘要 这项F31多样性提案使用我们的新型癌症研究了PDL 1在早期黑色素瘤进展中的作用。 原细胞原位小鼠模型。我们的总体假设是肿瘤内源性PDL 1信号 通过免疫和非免疫机制促进早期肿瘤进展。我们的提案将定义 在黑色素瘤细胞起源和已建立的黑色素瘤中新的细胞内在PDL 1信号提供了第一个 在不存在潜在混杂因素的情况下区分真正生物肿瘤-内源性PDL 1信号传导的模型 这是由于先前充满PDL 1的肿瘤细胞的遗传性PDL 1 KO的机制。我们将讨论这一假设 其目标如下: 目的1检验黑素细胞内源性PDL 1信号促进早期黑色素瘤进展的假设 和治疗敏感性。我们将研究黑素细胞固有的PDL 1信号,下游效应器, 使用PDL 1 KO TNQ 61 R小鼠模型,我们研究了UV暴露促进早期肿瘤进展的作用。 和同窝对照,其中PDL 1在黑素细胞中特异性缺失。转录组学(RNA-seq) 和蛋白质组学(Luminex,RPPA)动力学将随着黑素细胞从PDL 1无效良性进展而评估 痣到恶性黑色素瘤定义在癌变过程中何时出现PDL 1,并确定遗传 和蛋白质组学的环境管理PDL 1表达在体内和体外及其后果。PDL 1调节 致癌信号(例如,NRAS、BRAF、MEK、ERK、mTORC 1)将使用小分子抑制剂进行检测, 突变体NrasQ 61 R对WT Nras或BRAFV 600 E的体外CRISPR置换。免疫原性PDL 1抑制 将平行探索皮肤UV暴露后的STING信号,因为免疫原性机制是 定义,将在目标2中测试它们对从头肿瘤生长和治疗敏感性的贡献。 目的2定义黑素细胞内在PDL 1驱动进展和治疗脆弱性中的TME因素。 我们将使用我们的PDL 1 KO TNQ 61 R模型测试黑素细胞PDL 1依赖性TME免疫动力学, 随着时间的推移,非恶性皮肤和诱导的肿瘤,随着肿瘤随血流进展评估免疫群体 细胞仪免疫印迹、Luminex和qRT-PCR将测试免疫原性STING信号和趋化因子。 通过共聚焦成像评估离体产生和免疫细胞与肿瘤的共定位。替代 已知影响治疗功效的免疫原性途径(例如,焦亡,RIG-I/MAVS)将在 相似的时尚。PDL 1 KO TNQ 61 R小鼠和衍生细胞系的ICB、免疫细胞耗竭和 免疫缺陷小鼠测试PDL 1驱动的免疫依赖性靶向治疗弱点。免疫 PDL 1/Nras串扰的结果将被定义为对目标1中的信号传导研究的补充。

项目成果

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