PD-1/PD-L1 modulation in cancer therapy

在过去的十年中，对肿瘤免疫微环境的研究在小鼠模型和 人类已经确定了细胞内的信号通路和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 封闭抗体对各种进展期实体肿瘤有显著影响，并且 到目前为止，FDA已经批准了17种不同的疾病适应症。此外，免疫组织化学 我们早期研究中与抗PD-1抗体相关的肿瘤活检前组织中PD-L1的检测 临床反应，已被转化为目前批准用于特定癌症的4种不同的商业测试 确定治疗反应可能性增加的患者的类型。 目前的挑战是理解潜在的机制，这将在这项提案中得到解决 抗PD-(L)1在个体患者和跨癌症类型中的耐药性，影响到约80%的接受 这些毒品。为什么许多PD-L1+肿瘤患者对PD-1途径阻滞剂没有反应？为什么要 一些应答者后来复发了吗？为什么某些肿瘤类型对这种形式的 免疫疗法？ 在过去的R01资助期间，在表达调控方面有了重大发现 PD-1及其配体的研究，对识别生物标志物和发展组合 癌症免疫治疗的方法。PD-L1上调某些肿瘤的主要机制是 发现不是结构性诱导，而是适应性抵抗，肿瘤通过这种方式对 通过干扰素-g“感知”免疫威胁。相反，肿瘤细胞产生的一种主要细胞因子转化生长因子-b是 显示增强TCR驱动的PD-1启动子活性，从而增强T细胞上PD-1的表达，以及相关的 分子GARP和激活素受体1C被发现在维持Treg中起关键作用 TME中的免疫抑制。最后，通过无偏向基因确定肿瘤内源性耐药机制 表达谱分析成为抗PD-(L)1失败的关键决定因素。与此同时，取得了重大进展 在多维组织成像中使用所谓的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。 这一竞争性更新将通过解决三个问题来表征抗PD-(L)1肿瘤耐药的性质 目的：1)鉴定在PD-(L)1无反应者中选择性表达的Treg分子；2)定义肿瘤 介导抗PD-(L)1抵抗的细胞内源性途径；3)免疫细胞和 抗PD(L)1应答/耐药的基质因素。这些研究预计将翻译成 进入开发新的生物标志物和治疗组合，增强抗PD-(L)的疗效。

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.