PD-1/PD-L1 modulation in cancer therapy

癌症治疗中的 PD-1/PD-L1 调节

• 批准号: 10355495
• 负责人: DREW M. PARDOLL
• 金额: $ 58.81万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-21 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10355495
• 关键词: Activin Receptor; Address; Advanced Malignant Neoplasm; Affect; Aftercare; Antibodies; Archives; Area; Biological Markers; Biopsy; Blocking Antibodies; Cancer Patient; Cells; Clinic; Clinical; Complex; Core Biopsy; Data; Development; Dinoprostone; Disease; Elements; Enhancers; Excision; FDA approved; Failure; Formalin; Foundations; Funding; Gene Expression Profiling; Geography; Head and Neck Squamous Cell Carcinoma; Human; Image; Immune; Immune system; Immunofluorescence Immunologic; Immunohistochemistry; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Situ; In Vitro; Interferon Type II; Knock-in Mouse; Knock-out; Knowledge; LRRC32 gene; Laboratories; Lasers; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Membrane; Merkel cell carcinoma; Modeling; Molecular; Monoclonal Antibodies; Mus; Nature; Neoadjuvant Therapy; Operative Surgical Procedures; Outcome; PD-1 pathway; PD-1/PD-L1; PDL1 pathway; PTGS2 gene; Paraffin Embedding; Pathologic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Population; Process; Prostaglandin Receptor; Prostaglandins; RNA; Regimen; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Relapse; Resistance; Resolution; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Specimen; Structure; T-Lymphocyte; Technology; Testing; Tissue Stains; Tissue imaging; Tissues; Transforming Growth Factor beta; Translating; Tumor-infiltrating immune cells; Up-Regulation; activin A; anti-PD-1; anti-PD-L1; anti-PD1 therapy; anti-tumor immune response; antitumor effect; base; cancer immunotherapy; cancer therapy; cancer type; cell type; chemokine; clinical application; clinical translation; combinatorial; cytokine; data curation; imaging platform; immune resistance; in vivo; in vivo Model; in vivo evaluation; individual patient; inhibitor; melanoma; mouse model; neoplastic cell; next generation; novel; personalized immunotherapy; pre-clinical; programmed cell death ligand 1; programmed cell death protein 1; promoter; receptor; resistance mechanism; responders and non-responders; response; selective expression; small molecule; standard of care; therapy resistant; transcriptome sequencing; treatment response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

Over the past decade, studies of the immune microenvironment of cancer in both murine models and humans has identified intracellular signaling pathways and expression of membrane ligands and receptors that locally inhibit antitumor immune responses. Among the most important are the ligands PD-L1 and PD-L2 that interact with the co-inhibitory receptor PD-1 on activated immune cells. In the clinic, six unique PD-(L)1 blocking antibodies have had significant impact against a diverse range of advanced solid tumors, and have so far been approved by the FDA for 17 different disease indications. Furthermore, immunohistochemistry testing for PD-L1 expression in pretreatment tumor biopsies, correlated in our early studies with anti-PD-1 clinical response, has been translated into 4 different commercial tests currently approved in specific cancer types to identify patients with an increased likelihood of treatment response. The current challenge, which will be addressed in this proposal, is to understand mechanisms underlying anti-PD-(L)1 resistance in individual patients and across cancer types, affecting ~80% of patients receiving these drugs. Why do many patients with PD-L1+ tumors NOT respond to PD-1 pathway blockers? Why do some responders subsequently relapse? Why are some tumor types particularly resistant to this form of immunotherapy? During the past R01 funding period, major discoveries were made regarding regulation of the expression of PD-1 and its ligands, having important implications for identifying biomarkers and developing combinatorial approaches to cancer immunotherapy. A dominant mechanism for PD-L1 upregulation on certain tumors was revealed as not being constitutive induction but rather adaptive resistance, whereby tumors respond to “sensing” of immune threat through IFN-g. Conversely, a major cytokine produced by tumor cells, TGF-b, was shown to enhance TCR-driven PD-1 promoter activity and thus PD-1 expression on T cells, and the associated molecules GARP and Activin receptor type 1C were revealed to play pivotal roles in sustaining Treg immunosuppression in the TME. Finally, tumor-intrinsic resistance mechanisms identified by unbiased gene expression profiling emerged as critical determinants of anti-PD-(L)1 failure. In parallel, significant advances in multi-dimensional tissue imaging with the so-called “AstroPath” platform have revolutionized our ability to interrogate the TME, by capturing and analyzing spatially annotated quantitative data. This competing renewal will characterize the nature of anti-PD-(L)1 tumor resistance by addressing three Aims: 1) Identify Treg molecules selectively expressed in PD-(L)1 non-responders; 2) Define tumor cell-intrinsic pathways mediating anti-PD-(L)1 resistance; and 3) Characterize immune cell and stromal factors underlying anti-PD(L)1 response/resistance. These studies are anticipated to translate into the development of new biomarkers and treatment combinations, enhancing the efficacy of anti-PD-(L)1.

在过去的十年里，在小鼠模型和小鼠模型中对癌症免疫微环境的研究都是非常重要的。 人类已经鉴定了细胞内信号传导途径以及膜配体和受体的表达 局部抑制抗肿瘤免疫反应。其中最重要的是配体PD-L1和PD-L2 与激活的免疫细胞上的共抑制受体PD-1相互作用。在临床上，六种独特的PD-（L）1 阻断抗体对多种晚期实体瘤具有显著影响， 迄今为止，FDA已批准用于17种不同的疾病适应症。此外，免疫组织化学 在治疗前肿瘤活检中检测PD-L1表达，在我们的早期研究中与抗PD-1 临床反应，已转化为4种不同的商业测试，目前已批准在特定的癌症 类型，以识别治疗反应可能性增加的患者。 目前的挑战，这将在本提案中解决，是了解机制， 抗PD-（L）1耐药性在个体患者和跨癌症类型中，影响约80%接受 这些药物。为什么许多PD-L1+肿瘤患者对PD-1通路阻断剂无反应？为什么 一些反应者随后复发？为什么有些肿瘤类型对这种形式的 免疫疗法？ 在过去的R 01资助期间，关于表达调控的重大发现 PD-1及其配体，对于鉴定生物标志物和开发组合药物具有重要意义。 癌症免疫治疗的方法。某些肿瘤中PD-L1上调的主要机制是 显示不是组成性诱导，而是适应性抗性，由此肿瘤响应于 通过IFN-g“感知”免疫威胁。相反，肿瘤细胞产生的一种主要细胞因子TGF-β， 显示增强TCR驱动的PD-1启动子活性，从而增强T细胞上的PD-1表达，以及相关的 分子GARP和激活素受体1C型被揭示在维持Treg中起关键作用 TME中的免疫抑制。最后，通过无偏基因鉴定肿瘤内在耐药机制， 表达谱分析显示为抗PD-（L）1失败的关键决定因素。与此同时， 在多维组织成像与所谓的“AstroPath”平台已经彻底改变了我们的能力， 通过捕获和分析空间注释的定量数据来询问TME。 这种竞争性更新将通过解决三个问题来表征抗PD-（L）1肿瘤抗性的性质。 目的：1）鉴定在PD-（L）1无应答者中选择性表达的Treg分子; 2）定义肿瘤 介导抗PD-（L）1抗性的细胞内在途径;和3）表征免疫细胞， 抗PD（L）1应答/抗性的基质因子。这些研究预计将转化为 开发新的生物标志物和治疗组合，增强抗PD-（L）1的疗效。