Novel PD-L1 signals regulating anti-tumor immunity and immunotherapy responses

新型 PD-L1 信号调节抗肿瘤免疫和免疫治疗反应

• 批准号: 9440389
• 负责人: Curtis Clark
• 金额: $ 4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9440389
• 关键词: Address; Affect; Autophagocytosis; Biological Assay; Biological Response Modifiers; Blocking Antibodies; CCL2 gene; CD44 gene; CXCL12 gene; Cells; Clinical; Combined Modality Therapy; Data; Development; Distal; Distant; Engineering; FRAP1 gene; Failure; Growth; Immune; Immune Evasion; Immunity; Immunosuppression; Immunotherapy; In Vitro; Inflammatory; Knockout Mice; Lead; Link; Lymphocyte; Lymphocyte Function; Lymphocytic Infiltrate; Malignant Neoplasms; Malignant neoplasm of ovary; Mediation; Melanoma Cell; Modeling; Modification; Monoclonal Antibodies; Mus; Neoplasms; Outcome; Ovarian; PDCD1LG1 gene; Phenotype; Property; Regulation; Role; SLEB2 gene; Signal Transduction; Site; Stem Cell Development; Surface; T-Lymphocyte; Testing; Treatment Efficacy; Tumor Escape; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Tumorigenicity; anti-PD-1; anti-PD-L1; base; beta catenin; cancer cell; cancer immunotherapy; cancer stem cell; clinical efficacy; gene therapy; immune checkpoint; immune resistance; immunogenic; immunoregulation; in vivo; in vivo evaluation; innovation; insight; melanoma; mouse model; neoplasm immunotherapy; neoplastic cell; novel; public health relevance; response; stem-like cell; stemness; trafficking; transcriptome sequencing; treatment effect; treatment response; tumor; tumor microenvironment; tumor progression; tumorigenic

 DESCRIPTION (provided by applicant): Factors in the tumor microenvironment promote immunosuppression that permits tumor escape from immune destruction. Our data show that tumor PD-L1 (CD274, B7-H1) is a major regulator of tumor inflammatory lymphocyte (TIL) infiltrate. PD-L1 is widely expressed in many tumors and is the target of two successful new cancer immunotherapy approaches, but is a poor predictor of treatment efficacy. We define novel effects of tumor intrinsic PD-L1 signaling on tumor proliferation, cancer stem cell properties, in vivo growth independent of anti-tumor immunity, and regulation of mTOR signals and autophagy. We extend the concept of adaptive immune resistance by studying how tumor intrinsic PD-L1 alters anti-tumor immunity in vastly greater depth and detail than current studies that solely focus on the capacity of tumor PD-L1 to kill anti- tumor T cells. Despite the known role for PD-L1 in immunosuppression and the promising clinical benefits of αPD-L1 therapy, there remain significant gaps in understanding the role of tumor PD-L1 in the αPD-L1 response, immune modification, and tumorigenic potential through tumor intrinsic signaling. Our proposed studies will address these gaps by employing mouse models for ovarian cancers and melanoma cells that are PD-L1+ and engineered versions that are PD-L1lo or PD-L1-, and novel models of heterogeneous tumor PD-L1 expression to test our overarching hypothesis that anti-tumor immunity and response to αPD-L1 therapy are directed by tumor-intrinsic PD-L1 signals. We will address this hypothesis with the following specific aims: Specific Aim 1: Test the hypothesis that anti-tumor immunity and response to αPD-L1 therapy are modulated by heterogeneous tumor PD-L1 expression. We study mouse models for ovarian and melanoma tumors that are PD-L1+ and engineered versions that are PD-L1lo, PD-L1KO or PD-L1hi. We will employ B16 melanoma and ID8 ovarian cancer, along with PD-L1 KO mice, to define the mechanism of αPD-L1 therapy on anti-tumor TIL quantity and function, and determine which aspects of anti-tumor immunity are responsible for treatment effects of αPD-L1 in PD-L1lo/neg tumors. We will also define immune cell trafficking and T regulatory suppression effects altered by heterogeneous tumor PD-L1 expression with αPD-L1 therapy Specific Aim 2: Test the hypothesis that tumor PD-L1 regulation of tumor intrinsic mTOR and autophagy affects anti-tumor immunity and clinical outcomes. We will focus on control of tumor mTOR and autophagy (which are likely related) based on preliminary data, determining immune consequences by evaluating downstream effector molecules (e.g., CCL2, CCL9, CXCL12) using blocking antibodies and genetic interventions, and evaluate the impact on anti-tumor immunity in vivo. We will determine PD-L1 signals in stem cell development using validated in vitro and in vivo assays whether these properties are the result of PD-L1 regulation of tumor intrinsic signaling through mTOR and autophagy.

 描述（由申请人提供）：肿瘤微环境中的因子促进免疫抑制，使肿瘤逃避免疫破坏。我们的数据表明，肿瘤PD-L1（CD 274，B7-H1）是肿瘤炎性淋巴细胞（TIL）浸润的主要调节因子。PD-L1在许多肿瘤中广泛表达，是两种成功的新型癌症免疫治疗方法的靶点，但对治疗效果的预测效果较差。我们定义了肿瘤内源性PD-L1信号传导对肿瘤增殖、癌症干细胞特性、不依赖于抗肿瘤免疫的体内生长以及mTOR信号和自噬的调节的新作用。我们通过研究肿瘤内在PD-L1如何改变抗肿瘤免疫来扩展适应性免疫抗性的概念，其深度和细节远远超过目前仅关注肿瘤PD-L1杀死抗肿瘤T细胞的能力的研究。尽管已知PD-L1在免疫抑制中的作用以及αPD-L1治疗的有前景的临床获益，但在理解肿瘤PD-L1在αPD-L1应答、免疫修饰和通过肿瘤内在信号传导的致瘤潜力中的作用方面仍存在显著差距。 我们拟定的研究将通过采用PD-L1+和PD-L1 lo或PD-L1-的工程化版本的卵巢癌和黑色素瘤细胞的小鼠模型以及异质性肿瘤PD-L1表达的新型模型来验证我们的总体假设，即抗肿瘤免疫和对αPD-L1治疗的反应是由肿瘤内源性PD-L1信号指导的，来解决这些差距。我们将通过以下具体目的来解决这一假设：具体目的1：检验抗肿瘤免疫和对αPD-L1治疗的应答受异质性肿瘤PD-L1表达调节的假设。我们研究了PD-L1+和PD-L1 lo、PD-L1 KO或PD-L1 hi工程化版本的卵巢和黑色素瘤小鼠模型。我们将使用B16黑色素瘤和ID 8卵巢癌沿着PD-L1 KO小鼠，以确定αPD-L1治疗对抗肿瘤TIL数量和功能的机制，并确定抗肿瘤免疫的哪些方面负责αPD-L1在PD-L1 lo/neg肿瘤中的治疗效果。我们还将定义αPD-L1治疗异质性肿瘤PD-L1表达改变的免疫细胞运输和T调节抑制效应特定目的2：检验肿瘤PD-L1对肿瘤内在mTOR和自噬的调节影响抗肿瘤免疫和临床结局的假设。我们将基于初步数据专注于肿瘤mTOR和自噬（可能相关）的控制，通过评估下游效应分子（例如，CCL 2、CCL 9、CXCL 12），并评价对体内抗肿瘤免疫的影响。我们将使用经验证的体外和体内试验确定干细胞发育中的PD-L1信号，这些特性是否是PD-L1通过mTOR和自噬调节肿瘤内在信号传导的结果。