PD-L1 inhibition promotes type I interferon responses, enhancing chemotherapy-induced cytotoxicity in cancer cells

PD-L1 抑制促进 I 型干扰素反应，增强化疗诱导的癌细胞细胞毒性

• 批准号: 10621060
• 负责人: HyeonJoo Cheon
• 金额: $ 13.42万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621060
• 关键词: Advanced Malignant Neoplasm; Affect; Antibodies; Antineoplastic Agents; Binding Sites; Blocking Antibodies; Carboplatin; Cell Death; Cell Line; Cells; Cessation of life; Cisplatin; Clinical; Combined Modality Therapy; Data; Empiricism; Etoposide; FDA approved; Immune; Immune response; Immune system; Immunoglobulin G; Immunotherapy; In Vitro; Interferon Type I; Interferons; Life; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Monitor; Mus; Non-Small-Cell Lung Carcinoma; PDL1 inhibitors; Paclitaxel; Patients; Pharmaceutical Preparations; Phosphorylation; Reagent; Reporting; Resistance; Role; STAT1 gene; STAT2 gene; Signal Transduction; Structure; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Tyrosine Phosphorylation; Work; anti-PD-L1; anti-PD-L1 antibodies; anti-cancer; base; cancer cell; cancer therapy; cell killing; chemotherapeutic agent; chemotherapy; cytotoxicity; efficacy evaluation; gemcitabine; humanized monoclonal antibodies; immune checkpoint blockade; immunological status; improved; in vitro Model; in vivo; in vivo Model; innovation; knock-down; lung cancer cell; lung small cell carcinoma; neoplastic cell; pre-clinical; programmed cell death ligand 1; response

PROJECT SUMMARY Immune checkpoint blockade (ICB), for example using anti-PD-L1, is a landmark advance for treating advanced cancers but is nevertheless still effective in all too few patients. Thus, extensive efforts are directed at identifying combination therapeutic strategies to improve response rates. We have discovered that PD-L1, in addition to its role in blocking T cell activation, protects cancer cells against specific chemotherapeutic agents, e.g., cisplatin. Importantly, this mechanism operates independently of T cell recognition of tumor and the cell-extrinsic immune system. We found that PD-L1 inhibits the ability of cancer cells to respond to type I interferon (IFN-I) and that cancer cell-intrinsic responses to IFN-I are critical in increasing cisplatin cytotoxicity. We hypothesize that PD- L1 inhibitors will enhance the ability of IFN-I to sensitize cancer cells to chemotherapy by a cancer-cell intrinsic mechanism, independently of the immune system. Here, we propose to identify chemotherapeutic agents and IFN-I as logical drugs to combine with ICB, to increase response rates in an immune-independent manner. Aim 1. Determine the ability of the anti-PD-L1 ICB to enhance IFN-I responses and cisplatin toxicity in lung cancer cells. FDA-approved anti-PD-L1s (atezolizumab, avelumab, and durvalumab) are currently in clinical use to activate anti-cancer immune responses. However, it has not been assessed how efficiently each FDA-approved anti-PD-L1 blocks the cancer cell-intrinsic immune-independent function of PD-L1. We will determine which antibody against PD-L1 enhances IFNβ responses and cisplatin cytotoxicity in small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) cell lines, using Western analysis and IncuCyte real-time cell monitoring. Aim 2. Define the spectrum of therapeutic agents whose cytotoxicity is enhanced by inhibiting PD-L1. Each chemotherapeutic agent will be affected differently by the cancer cell-intrinsic function of PD-L1, since each induces cell death by different mechanisms. We will determine which chemotherapeutic agent kills cancer cells more efficiently in combination with PD-L1 inhibition (knock-down of PD-L1 or treating with selected antibodies against PD-L1) alone, or by using PD-L1 inhibition plus IFN-I in SCLC cells. Aim 3. Generate pre-clinical in vivo proof of principle for rational combination therapy. After selecting the most efficient combination in vitro in SCLC and NSCLC cell lines, we will evaluate the efficacy of the combination treatment in vivo in NSG mice, which lack most of the immune system, to cleanly evaluate the cancer cell-intrinsic immune-independent PD-L1-mediated effects. Impact. The studies proposed here are highly innovative as they propose a paradigm-shifting approach in which PD-L1 inhibitors are used as reagents to enhance the ability of IFN-I to sensitize cancer cells to chemotherapy in an immune-independent mechanism. This work will lead to improved understanding of a relatively unexplored facet of anti-PD-L1 activity, in ways that will lead to rational combination treatments for patients, regardless of their pre-existing immune status, to hopefully meaningfully increase response rates.

项目总结 免疫检查点阻断(ICB)，例如使用抗PD-L1，是治疗晚期癌症的一个里程碑式的进步 癌症，但仍然对太少的患者有效。因此，广泛的努力旨在确定 综合治疗策略以提高应答率。我们发现PD-L1除了它的 在阻断T细胞激活中的作用，保护癌细胞免受特定化疗药物的影响，例如顺铂。 重要的是，这种机制独立于T细胞对肿瘤的识别和细胞-外源性免疫 系统。我们发现PD-L1抑制癌细胞对I型干扰素(IFN-I)的反应能力，并且 肿瘤细胞对干扰素-I的本征反应是增加顺铂细胞毒性的关键。我们假设警局- L1抑制剂将增强干扰素-I通过一种癌细胞固有的方式使癌细胞对化疗敏感的能力 机制，独立于免疫系统。在这里，我们建议确定化疗药物和 干扰素-I作为合理的药物与ICB结合，以免疫非依赖性的方式提高应答率。 目的1.检测抗PD-L1ICB增强人干扰素-I应答和顺铂毒性的能力。 肺癌细胞。FDA批准的抗PD-L1s(atezolizumab、Avelumab和duvalumab)目前正在治疗中 临床上用于激活抗癌免疫反应。然而，还没有评估它们各自的效率 FDA批准的抗PD-L1阻断了PD-L1的癌细胞固有免疫独立功能。我们会 测定抗PD-L1抗体增强干扰素β应答和顺铂对小细胞肺的细胞毒作用 肺癌(SCLC)和非小细胞肺癌(NSCLC)细胞系的Western分析和IncuCyte 实时细胞监测。目标2.定义其细胞毒性增强的治疗药物的光谱 通过抑制PD-L1。每种化疗药物都会受到固有癌细胞的不同影响 PD-L1的功能，因为每一种都通过不同的机制诱导细胞死亡。我们将确定哪一个 化疗药物结合PD-L1抑制更有效地杀死癌细胞(击倒 PD-L1或用选定的抗PD-L1抗体治疗)，或在小细胞肺癌中使用PD-L1抑制加干扰素-I治疗 细胞。目的3.为合理的联合治疗提供临床前的体内原则证明。之后 在体外选择SCLC和NSCLC细胞系中最有效的组合，我们将评估其疗效 在体内联合治疗缺乏大部分免疫系统的NSG小鼠，以干净地评估 癌细胞固有免疫非依赖PD-L1介导的效应。 冲击力。这里提出的研究具有很高的创新性，因为他们提出了一种范式转换的方法，其中 PD-L1抑制剂用作试剂以增强干扰素-I使癌细胞对化疗增敏的能力 在一种免疫独立的机制中。这项工作将有助于加深对一种相对未探索的 抗PD-L1活性的方面，将导致患者的合理组合治疗，无论 他们先前存在的免疫状态，希望能有意义地提高应答率。