PD-1/PD-L1 modulation in cancer therapy

癌症治疗中的 PD-1/PD-L1 调节

基本信息

批准号：
9188057
负责人：
DREW M. PARDOLL
金额：
$ 48.83万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-21 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9188057
关键词：
Antigens Automobile Driving Autopsy B7-DC antigen Biological Biological Markers Blocking Antibodies Cells Clinical Combined Modality Therapy Common Neoplasm Development Disease Epigenetic Process Funding Genetic Grant Head Cancer Hodgkin Disease Human Immune Immune response Immune system Immunity Immunologics Immunotherapy In Situ Hybridization In Vitro Interferon Type II Knowledge Lesion Ligands Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of urinary bladder Membrane Molecular Mus Neck Cancer Neoplasm Metastasis Outcome PDCD1LG1 gene Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phosphorylation Process Regulation Regulatory T-Lymphocyte Renal carcinoma Resistance Resistance development Role Signal Pathway Signal Transduction Signaling Molecule Solid Neoplasm Specimen System T-Lymphocyte Testing Thinking Tissues Transforming Growth Factor beta Tumor-Infiltrating Lymphocytes Up-Regulation Ursidae Family base biomarker development biomarker-driven cancer cell cancer immunotherapy cancer therapy cell type clinical application clinical development clinical effect clinical practice combinatorial cytokine digital human tissue immune resistance immunological diversity in vivo in vivo Model individual patient innovation melanoma mouse model neoplastic cell overexpression predicting response programs promoter public health relevance receptor research clinical testing resistance mechanism responders and non-responders response spectrograph tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Over the past 10 years, studies of the immune microenvironment of cancer in both murine models and in 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 T cells. PD-1 pathway-blocking antibodies have so far had significant impact in melanoma, renal, lung, bladder, head and neck, and ovarian cancers, and Hodgkin's lymphoma. During the initial R01 funding period, we have made major discoveries regarding regulation of the expression of PD-1 and its ligands, that have important implications for identifying biomarkers and developing combinatorial approaches to cancer immunotherapy. Specifically, we showed that PD-L1 expression in tumors predicts response to PD-1 blockade. This finding has led to the development of PD-L1 IHC tests by several major pharmaceutical companies developing PD-1 pathway blocking drugs. We also demonstrated coordinate expression of PD-L1 and other checkpoint molecules, supporting the clinical development of the anti-PD-1/LAG-3 combination. Finally, we developed major biological and molecular concepts for understanding regulation of PD-1 and its ligands in the tumor microenvironment (TME), namely that expression represents a dynamic cross- talk between tumor cells and TILs. We showed that a dominant mechanism for PD-L1 up-regulation on certain tumors is not constitutive induction but rather adaptive resistance, whereby tumors respond to "sensing" of immune threat through IFN-g. The adaptive resistance concept now guides thinking in the field. Conversely, we also showed that a major cytokine produced by tumor cells, TGF-b, can enhance TCR-driven PD-1 promoter activity and thus PD-1 expression on T cells. These discoveries from our previous grant period raise a number of additional questions that bear on advances in immunotherapy: Why do some tumor types express PD-L1 adaptively and others constitutively? What are the relative functional roles of PD-L1 expression by tumor cells vs. infiltrating immune cells? Is the expression of PD-1 on TILs regulated in vivo by levels of TGF-b and TGF-b dependent signaling molecules? How heterogeneous is expression of PD-1, PD-L1 and other coordinately regulated checkpoint molecules among metastases in a given patient? Why do many patients with PD-L1+ tumors NOT respond to PD-1 pathway blockers? To answer these questions, we propose three Aims in this competing renewal: 1) Define mechanisms regulating PD-L1 expression by tumor cells and other cell types in the TME; 2) Characterize factors influencing PD-1 expression by T cells; and 3) Characterize immunological mechanisms underlying the clinical effects of PD-L1/PD-1 blockade in cancer therapy, including the co-expression of multiple checkpoint pathways that might provide resistance pathways to therapy.

描述（由适用提供）：在过去的10年中，在鼠模型和人类中对癌症免疫微环境的研究已经鉴定出细胞内信号通路以及膜配体和受体的表达，这些膜配体和受体局部抑制了抗肿瘤免疫剂。最重要的是与激活的T细胞上的共抑制受体PD-1相互作用的配体PD-L1和PD-L2。迄今为止，PD-1途径阻断抗体对黑色素瘤，肾脏，肺，膀胱，头颈以及卵巢癌以及霍奇金的淋巴瘤产生了重大影响。在最初的R01资金期间，我们对调节PD-1及其配体的表达有了重大发现，这些发现对鉴定生物标志物和开发癌症免疫疗法的组合方法具有重要意义。具体而言，我们表明肿瘤中的PD-L1表达预测了对PD-1阻滞的反应。这一发现导致了几家开发PD-1途径阻断药物的主要制药公司开发PD-L1 IHC测试。我们还证明了PD-L1和其他检查点分子的坐标表达，支持抗PD-1/LAG-3组合的临床发育。最后，我们开发了主要的生物学和分子概念，用于理解肿瘤微环境（TME）中PD-1及其配体的调节，即表达代表肿瘤细胞和TIL之间的动态串扰。我们表明，在某些肿瘤上上调的PD-L1上调的主要机制不是构成诱导，而是适应性抗性，从而通过IFN-G对肿瘤的“感知”响应。自适应抗性概念现在指导了该领域的思维。相反，我们还表明，由肿瘤细胞TGF-B产生的主要细胞因子可以增强TCR驱动的PD-1启动子活性，从而增强T细胞上的PD-1表达。这些发现从我们以前的赠款期间提出了许多其他问题，这些问题对免疫疗法的进步提出了一些问题：为什么某些肿瘤类型可以适应PD-L1而构成构成？肿瘤细胞与浸润免疫细胞的PD-L1表达的相对功能作用是什么？ PD-1在TILS上的表达是否由TGF-B和TGF-B依赖性信号分子的水平调节体内？在给定患者中，PD-1，PD-L1和其他协调调控的检查点分子的表达如何？为什么许多PD-L1+肿瘤患者对PD-1途径阻滞剂没有反应？为了回答这些问题，我们提出了这种竞争更新中的三个目标：1）定义机制，确定肿瘤细胞和TME中其他细胞类型的PD-L1表达； 2）特征因素影响T细胞的PD-1表达； 3）表征PD-L1/PD-1阻断癌症治疗中临床作用的背后的免疫机制，包括共表达多种检查点途径，这些途径可能提供治疗的抗药性途径。