PD-1/PD-L1 modulation in cancer therapy

 描述（由申请人提供）：在过去10年中，对小鼠模型和人体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应答的膜配体和受体的表达。其中最重要的是与活化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通路阻断抗体在黑色素瘤、肾癌、肺癌、膀胱癌、头颈癌和卵巢癌以及霍奇金淋巴瘤中具有显著影响。在最初的R 01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。具体而言，我们发现肿瘤中的PD-L1表达预测了对PD-1阻断的反应。这一发现促使几家主要制药公司开发PD-1通路阻断药物，开发PD-L1 IHC检测。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，我们开发了用于理解肿瘤微环境（TME）中PD-1及其配体的调节的主要生物学和分子概念，即表达代表肿瘤细胞和TIL之间的动态串扰。我们发现，PD-L1在某些肿瘤上上调的主要机制不是组成性诱导，而是适应性抗性，肿瘤通过IFN-g对免疫威胁的“感知”作出反应。适应性抗性概念现在指导着该领域的思考。相反，我们还表明，肿瘤细胞产生的主要细胞因子TGF-β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。我们上一个资助期的这些发现提出了一些与免疫治疗进展有关的额外问题：为什么某些肿瘤类型适应性表达PD-L1，而另一些则是组成性表达？肿瘤细胞与浸润性免疫细胞表达PD-L1的相对功能作用是什么？体内TIL上PD-1的表达是否受TGF-β和TGF-β依赖性信号分子水平的调节？在特定患者的转移瘤中，PD-1、PD-L1和其他协调调节的检查点分子的表达有多异质？为什么许多PD-L1+肿瘤患者对PD-1通路阻断剂无反应？为了回答这些问题，我们提出了三个目标：1）确定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;和3）表征PD-L1/PD-1阻断在癌症治疗中的临床作用的免疫学机制，包括可能提供对治疗的抗性途径的多个检查点途径的共表达。

 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.