State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong 264000, China.
Sci Immunol. 2019 Jul 12;4(37). doi: 10.1126/sciimmunol.aau6584.
Immunological tolerance of tumors is characterized by insufficient infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive microenvironment of tumor. Tumor resistance to immune checkpoint inhibitors due to immunological tolerance is an ongoing challenge for current immune checkpoint blockade (ICB) therapy. Here, we report the development of tumor microenvironment-activatable anti-PDL1 antibody (αPDL1) nanoparticles for combination immunotherapy designed to overcome immunological tolerance of tumors. Combination of αPDL1 nanoparticle treatment with near-infrared (NIR) laser irradiation-triggered activation of photosensitizer indocyanine green induces the generation of reactive oxygen species, which promotes the intratumoral infiltration of CTLs and sensitizes the tumors to PDL1 blockade therapy. We showed that the combination of antibody nanoparticles and NIR laser irradiation effectively suppressed tumor growth and metastasis to the lung and lymph nodes in mouse models. The nanoplatform that uses the antibody nanoparticle alone both for immune stimulation and PDL1 inhibition could be readily adapted to other immune checkpoint inhibitors for improved ICB therapy.
肿瘤的免疫耐受特点为细胞毒性 T 淋巴细胞（CTLs）浸润不足和肿瘤的免疫抑制微环境。由于免疫耐受，肿瘤对免疫检查点抑制剂的耐药性是当前免疫检查点阻断（ICB）治疗的一个持续挑战。在这里，我们报告了用于联合免疫治疗的肿瘤微环境激活型抗 PD-L1 抗体（αPDL1）纳米颗粒的开发，旨在克服肿瘤的免疫耐受。将 αPDL1 纳米颗粒治疗与近红外（NIR）激光照射触发的光敏剂吲哚菁绿的激活相结合，诱导活性氧的产生，促进 CTLs 向肿瘤内浸润，并使肿瘤对 PD-L1 阻断治疗敏感。我们表明，抗体纳米颗粒与 NIR 激光照射的联合治疗有效地抑制了小鼠模型中的肿瘤生长和肺及淋巴结转移。该纳米平台既可以用于免疫刺激，也可以用于 PD-L1 抑制，可很容易地适应其他免疫检查点抑制剂，以改善 ICB 治疗。
