Stimuli-responsive Delivery of Ectonucleotidase Inhibitors to Reprogram Immunometabolism in Head and Neck Cancer

刺激响应性递送外核苷酸酶抑制剂以重编程头颈癌的免疫代谢

• 批准号: 10589885
• 负责人: Xin Ming
• 金额: $ 17.75万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589885
• 关键词: Acids; Address; Adenosine; Cancer Etiology; Cell Death; Cells; Cellular Stress; Clinical; Combination immunotherapy; Cytometry; Development; Disease; Drug Delivery Systems; Drug Targeting; Enzymes; Equilibrium; Extracellular Space; Goals; HPV-negative head and neck cancer; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Human body; Immune; Immunity; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Inflammation; Light; Link; Malignant Neoplasms; Mediating; Modeling; Mus; Normal tissue morphology; Nucleotides; PD-1 blockade; PUVA Photochemotherapy; Pharmaceutical Preparations; Photosensitizing Agents; Physiological; Play; Public Health; Reactive Oxygen Species; Regimen; Research; Resistance; Role; Scheme; Signal Transduction; Site; Solid Neoplasm; Specificity; Stimulus; System; Toxic effect; Tumor Immunity; anti-cancer; anticancer activity; body system; cancer cell; cancer immunotherapy; cancer therapy; carcinogenesis; clinical translation; drug action; ecto-nucleotidase; extracellular; human disease; immune activation; immune checkpoint blockade; immunogenic; immunogenic cell death; inhibitor; irradiation; mouse model; nanoparticle; neoplastic cell; next generation; novel strategies; nucleotide analog; personalized approach; prevent; programs; purine metabolism; recruit; response; tumor; tumor microenvironment

Summary Therapy-induced cancer immunity is limited by immunosuppressive mechanisms posed by the tumor microenvironment (TME). Cancer therapy triggers ATP release from cancer cells during the course of immunogenic cell death and extracellular ATP plays a pivotal role in the initiation of antitumor immunity by acting as a danger signal. However, extracellular ATP is quickly degraded into immunosuppressive adenosine via the concerted enzymatic activities of CD39 and CD73, dampening anticancer immunity. Systemic blockage of these enzymes often causes toxicity in normal tissues, where they protect the host from excessive immune activation. We hypothesize that stimuli-responsive delivery of CD39/CD73 inhibitors reprograms immunometabolism selectively in the TME, leading to effective and specific anticancer immunity without generating immune- mediated toxicity. We have prepared phenylboronic acid (PBA)-containing nanoparticles (NPs) for stimuli- responsive drug delivery. CD39 inhibitor ARL67156 (ARL), a nucleotide analogue, was loaded to the NPs through the interaction with PBA. The nucleotide drug can be released from the NPs through reactive oxygen species (ROS)-mediated degradation of PBA. Thus, we further loaded a photosensitizer IR700 on the NPs. Irradiation of the NPs with NIR light produced ROS that triggered ARL release from the NPs. On the other hand, photodynamic therapy (PDT) of tumor cells with the NPs caused extracellular ATP release. The released ARL prevented conversion of ATP to adenosine, thereby extending the immunogenic actions by PDT-released ATP and preventing adenosine-mediated immunosuppression. This change of immunometabolism landscape in the TME led to excellent tumor response in a mouse model of head and neck cancers that is resistant to immune checkpoint blockade. In this proposal, we will explore the mechanisms for TME reprograming after tumor delivery of ARL (Aim 1), and will enhance anticancer activity of CD39 inhibition by combination with other cancer immunotherapy for treating immunosuppressive tumors of head and neck cancers (Aim 2). Successful implementation of this project will ultimately lead to highly cancer specific and versatile delivery systems for cancer immunotherapy. By addressing lack of cancer specificity, a main obstacle for the development of next- generation immunotherapeutic regimens, we will contribute to a novel approach for precision delivery of immunotherapy.

概括 治疗诱导的癌症免疫受到肿瘤引起的免疫抑制机制的限制 微环境（TME）。癌症治疗过程中会触发癌细胞释放 ATP 免疫原性细胞死亡和细胞外 ATP 通过作用在抗肿瘤免疫的启动中发挥着关键作用 作为危险信号。然而，细胞外 ATP 通过 CD39和CD73协同酶活性，抑制抗癌免疫力。这些系统性阻塞 酶通常会在正常组织中引起毒性，从而保护宿主免受过度的免疫激活。 我们假设 CD39/CD73 抑制剂的刺激响应性递送会重新编程免疫代谢 选择性地进入 TME，从而产生有效且特异性的抗癌免疫力，而不产生免疫- 介导的毒性。我们制备了含有苯硼酸（PBA）的纳米颗粒（NP）用于刺激 响应性药物递送。 CD39 抑制剂 ARL67156 (ARL)（一种核苷酸类似物）被加载到纳米颗粒上 通过与PBA的交互。核苷酸药物可以通过活性氧从纳米颗粒中释放出来 物种（ROS）介导的 PBA 降解。因此，我们进一步在纳米粒子上负载光敏剂 IR700。 用近红外光照射 NP 会产生 ROS，从而触发 NP 释放 ARL。另一方面， 使用纳米粒子对肿瘤细胞进行光动力疗法（PDT）引起细胞外 ATP 释放。发布的ARL 阻止 ATP 转化为腺苷，从而延长 PDT 释放的 ATP 的免疫原性作用 并预防腺苷介导的免疫抑制。免疫代谢格局的这种变化 TME 在对免疫具有抵抗力的头颈癌小鼠模型中产生了良好的肿瘤反应 检查站封锁。在本提案中，我们将探讨肿瘤递送后 TME 重编程的机制 ARL（目标1），并通过与其他癌症组合增强CD39抑制的抗癌活性 用于治疗头颈癌免疫抑制肿瘤的免疫疗法（目标 2）。成功的 该项目的实施最终将导致高度癌症特异性和多功能的输送系统 癌症免疫疗法。通过解决缺乏癌症特异性的问题，这是开发下一代药物的主要障碍 一代免疫治疗方案，我们将致力于开发一种精确递送的新方法 免疫疗法。