PD-1/PD-L1 modulation in cancer therapy

癌症治疗中的 PD-1/PD-L1 调节

• 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
• 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

 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（由申请人提供）：在过去的 10 年里，对小鼠模型和人类癌症免疫微环境的研究已经确定了细胞内信号传导途径以及局部抑制抗肿瘤免疫反应的膜配体和受体的表达。其中最重要的是配体 PD-L1 和 PD-L2，它们与活化 T 细胞上的共抑制受体 PD-1 相互作用。迄今为止，PD-1 通路阻断抗体对黑色素瘤、肾癌、肺癌、膀胱癌、头颈癌、卵巢癌以及霍奇金淋巴瘤具有显着影响。在最初的 R01 资助期间，我们在 PD-1 及其配体的表达调控方面取得了重大发现，这对于识别生物标志物和开发癌症免疫治疗的组合方法具有重要意义。具体来说，我们发现肿瘤中的 PD-L1 表达可以预测对 PD-1 阻断的反应。这一发现促使几家开发 PD-1 通路阻断药物的主要制药公司开发了 PD-L1 IHC 测试。我们还证明了 PD-L1 和其他检查点分子的协调表达，支持抗 PD-1/LAG-3 组合的临床开发。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。我们发现，某些肿瘤上 PD-L1 上调的主要机制不是组成型诱导，而是适应性抵抗，即肿瘤通过 IFN-g 对“感知”免疫威胁做出反应。适应性抵抗概念现在指导着该领域的思考。相反，我们还发现肿瘤细胞产生的主要细胞因子 TGF-b 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。我们之前资助期间的这些发现提出了一些与免疫治疗进展相关的其他问题：为什么某些肿瘤类型适应性表达 PD-L1，而其他肿瘤类型则组成型表达？肿瘤细胞与浸润免疫细胞表达的 PD-L1 的相对功能作用是什么？ TIL 上 PD-1 的表达在体内受 TGF-b 和 TGF-b 依赖性信号分子水平的调节吗？特定患者的转移灶中 PD-1、PD-L1 和其他协调调节的检查点分子的表达有何异质性？为什么许多 PD-L1+ 肿瘤患者对 PD-1 通路阻断剂没有反应？为了回答这些问题，我们在这一竞争性更新中提出了三个目标：1）定义 TME 中肿瘤细胞和其他细胞类型调节 PD-L1 表达的机制； 2）表征影响T细胞表达PD-1的因素； 3) 表征癌症治疗中 PD-L1/PD-1 阻断的临床效果背后的免疫学机制，包括可能提供治疗耐药途径的多个检查点途径的共表达。