Mild hyperthermia promotes immune checkpoint blockade-based immunotherapy against metastatic pancreatic cancer using size-adjustable nanoparticles
Mild hyperthermia promotes immune checkpoint blockade-based immunotherapy against metastatic pancreatic cancer using size-adjustable nanoparticles
复制标题
轻度热疗可促进基于免疫检查点阻断的免疫疗法，使用尺寸可调的纳米粒子来对抗转移性胰腺癌。
DOI：
10.1016/j.actbio.2021.05.002
复制
发表时间：
2021-10-03
影响因子：
9.7
通讯作者：
He, Qin
中科院分区：
文献类型：
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作者：
Yu, Qianwen;Tang, Xian;He, Qin
免疫检查点阻断治疗是最有前途的免疫疗法之一，其在抑制转移方面显示出有希望的治疗效果。然而，由于胰腺癌广泛的纤维化基质和免疫抑制性肿瘤微环境，免疫治疗对胰腺癌的影响很小。光热疗法（photothermal therapy，PTT）诱导的轻度热疗可激活肿瘤微环境中的免疫反应。在此，我们设计了一种使用尺寸可调节的热和纤维化基质敏感脂质体（HSA-BMS@CAP-ILTSL）的轻度高温和免疫检查点阻断（BMS-202）治疗的联合收割机策略，其中包封了BMS-202负载的小尺寸白蛋白纳米颗粒（HSA-BMS）。轻度热疗可减轻肿瘤缺氧，降低间质压力，促进内源性免疫细胞的募集。与此同时，在成纤维细胞活化蛋白-α（FAP-α）和近红外（NIR）激光的作用下，小尺寸HSA-BMS从大尺寸HSA-BMS@CAP-ILTSL中释放出来，并通过恢复T淋巴细胞的活性来增强免疫应答，同时分泌相关的细胞因子（TNF-α和IFN-γ）。联合治疗（HSA-BMS@CAP-ILTSL）不仅能显著抑制体内肿瘤生长，而且能减少远处器官转移结节的数量。这些结果表明，尺寸可调的纳米粒子在治疗转移性胰腺癌方面具有很大的潜力。重要性声明胰腺癌的促结缔组织增生间质和低灌注给有效的治疗（包括化疗、放疗、靶向治疗和免疫治疗）带来了物理障碍。我们构建了尺寸约为120 nm的尺寸可调节的热和纤维化基质敏感脂质体（HSA-BMS@CAP-ILTSL），其中小尺寸的免疫检查点抑制剂（HSA-BMS）的白蛋白纳米颗粒（10 nm）包封在内部。轻度热疗不仅有助于释放HSA-BMS用于穿透（阻断肿瘤深处的免疫抑制信号），而且增强肿瘤血液灌注用于内源性免疫细胞的浸润。在双管齐下的治疗中，胰腺癌免疫治疗显著增强，癌症转移的风险降低。总体而言，该策略提供了一种有希望的方法来增加药物蓄积并提高胰腺癌中的抗肿瘤免疫活性。(C)2021 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Immune checkpoint blockade treatment is one of the most promising immunotherapies, which exhibits promising therapeutic effects on inhibition of metastasis. However, immunotherapy has little effect on pancreatic cancer, due to its extensive fibrotic matrix and immunosuppressive tumor microenvironment. Mild hyperthermia induced by photothermal therapy (PTT) has been proven to activate the immune responses in the tumor microenvironment. Herein, we designed a combine strategy of mild hyperthermia and immune checkpoint blockade (BMS-202) treatment with size-adjustable thermo- and fibrotic matrix-sensitive liposomes (HSA-BMS@CAP-ILTSL), in which BMS-202 loaded small-sized albumin nanoparticle (HSA-BMS) was encapsulated. Mild hyperthermia reduced the tumor hypoxia, relieved the interstitial pressure and increased the recruitment of endogenous immune cells in tumors. In the meantime, smallsized HSA-BMS was released from large-sized HSA-BMS@CAP-ILTSL in response to fibroblast activation protein-alpha (FAP-alpha) and near-infrared (NIR) laser, and enhanced the immunological responses by recovering the activity of T lymphocytes, accompanied by secreting relevant cytokines (TNF-alpha and IFN-gamma). The combined therapy (HSA-BMS@CAP-ILTSL) could not only significantly suppress the tumor growth in vivo, but also decrease the amounts of metastatic nodules in distant organs. These results suggested that size-adjustable nanoparticles had a great potential in the treatment of metastatic pancreatic cancer.Statement of significanceThe desmoplastic stroma and hypoperfusion of pancreatic cancer imposed physical barriers to effective therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We constructed size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL) with size around 120 nm, where small sized albumin nanoparticle (10 nm) of immune checkpoint inhibitor (HSA-BMS) were encapsulated inside. Mild hyperthermia not only contributed to release HSA-BMS for penetration (blocking the immunosuppressive signals deep in the tumor), but enhanced tumor blood perfusion for infiltration of endogenous immune cells. In the two-pronged treatment, the pancreatic cancer immunotherapy significantly enhanced and the risk of cancer metastasis was reduced. Overall, the strategy provides a promising approach to increase drug accumulation and improve the anti-tumor immune activity in pancreatic cancer. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.