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 这份F31-多样性提案使用我们的新型癌症研究了PDL1在早期黑色素瘤进展中的作用 自体细胞来源的小鼠模型。我们的主要假设是肿瘤固有的PDL1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 黑色素瘤细胞起源和已建立的黑色素瘤中新的细胞固有PDL1信号提供了第一个 在没有潜在混杂的情况下区分真实的生物肿瘤固有PDL1信号的模型 先前充满PDL1的肿瘤细胞遗传PDL1KO的机制我们将解决这一假设 目标如下: 目的1验证黑素细胞固有的PDL1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PDL1信号,下游效应因子,以及 紫外线照射促进PDL1KO TNQ61R小鼠模型早期肿瘤进展的作用 建立和产仔对照,其中PDL1在黑素细胞中被特异性删除。转录(RNA-seq) 蛋白质组(Luminex,RPPA)的动力学将随着黑素细胞从PDL1缺失的良性进展而被评估 色素痣到恶性黑色素瘤定义PDL1在癌变过程中何时出现并确定其基因 以及蛋白质组环境控制PDL1在体内和体外的表达及其后果。PDL1调节 致癌信号(例如,NRAS、BRAF、MEK、ERK、mTORC1)将使用小分子抑制剂和 用突变的NRASQ61R体外CRISPR替换WT NRAS或BRAFV600E。PDL1对免疫原性的抑制 皮肤紫外线照射后的刺痛信号将被并行探索,免疫原性机制也将被 确定,它们对新生肿瘤生长和治疗敏感性的贡献将在目标2中进行测试。 目的2明确TME因素在黑素细胞固有的PDL1驱动进展和治疗易感性中的作用。 我们将使用我们的PDL1KO TNQ61R模型通过采集 随着时间的推移,非恶性皮肤和诱导的肿瘤,随着肿瘤的进展评估免疫种群 细胞学。免疫印迹、Luminex和qRT-PCR将测试免疫原性刺痛信号和趋化因子 体外生产和免疫细胞与肿瘤的共定位将通过共聚焦成像进行评估。备择 将在#年研究已知的影响治疗效果的免疫原性途径(例如,上睑下垂、RIG-I/MAV)。 相似的款式。PDL1KO TNQ61R小鼠及其衍生细胞系ICB、免疫细胞耗竭和免疫抑制的研究 免疫缺陷小鼠测试PDL1驱动的免疫依赖靶向治疗漏洞。免疫 PDL1/NRAS串扰的结果将被定义为对目标1中的信令研究的补充。

项目成果

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