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.

项目概要 免疫检查点阻断 (ICB)，例如使用抗 PD-L1，是治疗晚期癌症的里程碑式进展 癌症，但仍然对极少数患者有效。因此，广泛的努力旨在确定 联合治疗策略以提高缓解率。我们发现 PD-L1 除了 阻断 T 细胞激活，保护癌细胞免受特定化疗药物（例如顺铂）的侵害。 重要的是，这种机制的运作独立于 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 抑制癌细胞响应 I 型干扰素 (IFN-I) 的能力，并且 癌细胞对 IFN-I 的内在反应对于增加顺铂的细胞毒性至关重要。我们假设 PD- L1 抑制剂将增强 IFN-I 通过癌细胞内在的化学物质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 IFN-I 作为与 ICB 结合的合理药物，以不依赖于免疫的方式提高应答率。 目标 1. 确定抗 PD-L1 ICB 增强 IFN-I 反应和顺铂毒性的能力 肺癌细胞。 FDA 批准的抗 PD-L1（atezolizumab、avelumab 和 durvalumab）目前正在研究中 临床用于激活抗癌免疫反应。然而，尚未评估每个项目的效率如何 FDA 批准的抗 PD-L1 药物可阻断 PD-L1 的癌细胞固有的免疫独立功能。我们将 确定哪种抗 PD-L1 抗体可增强小细胞肺中的 IFNβ 反应和顺铂细胞毒性 癌 (SCLC) 和非小细胞肺癌 (NSCLC) 细胞系，使用 Western 分析和 IncuCyte 实时细胞监测。目标 2. 确定细胞毒性增强的治疗药物谱 通过抑制 PD-L1。每种化疗药物都会受到癌细胞固有的不同影响 PD-L1 的功能，因为每种细胞通过不同的机制诱导细胞死亡。我们将确定哪个 化疗药物与 PD-L1 抑制（敲低 PD-L1 或单独使用选定的抗 PD-L1 抗体治疗，或在 SCLC 中使用 PD-L1 抑制加 IFN-I 进行治疗 细胞。目标 3. 生成合理联合治疗的临床前体内原理证明。后 在 SCLC 和 NSCLC 细胞系中选择体外最有效的组合，我们将评估其功效 在缺乏大部分免疫系统的 NSG 小鼠体内进行联合治疗，以清晰地评估 癌细胞固有的免疫独立性 PD-L1 介导的效应。 影响。这里提出的研究具有高度创新性，因为它们提出了一种范式转换方法，其中 PD-L1抑制剂用作增强IFN-I使癌细胞对化疗敏感的能力的试剂 在一种独立于免疫的机制中。这项工作将有助于加深对相对未经探索的领域的理解 抗 PD-L1 活性的各个方面，以多种方式为患者提供合理的联合治疗，无论 他们预先存在的免疫状态，希望能够有意义地提高反应率。