Hao Yang, Chung Chih Kit, Gu Zili, Schomann Timo, Dong Xiaoxu, Veld Ruben V Huis In 't, Camps Marcel G M, Ten Dijke Peter, Ossendorp Ferry A, Cruz Luis J
Translational Nanobiomaterials and Imaging (TNI) Group, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
JeNaCell GmbH, Winzerlaer Straße 2, 07745, Jena, Germany.
Mol Biomed. 2022 Aug 17;3(1):26. doi: 10.1186/s43556-022-00086-z.
Photodynamic therapy (PDT) has shown impressive therapeutic effects on various types of cancers by reactive oxygen species (ROS) generation and induction of immune responses. However, under certain conditions, the immune responses induced by PDT are not always sufficient to eradicate the remaining tumor cells. On the other hand, the photosensitizer indocyanine green (ICG) can mediate PDT under near-infrared (NIR) illumination, thereby enhancing the penetration depth of the excitation light into the tumor. We found that ICG is rapidly taken up in vitro by colorectal MC38 and CT26 tumor cells and it promotes PDT-mediated cell-killing effects. Our results furthermore revealed that ICG induces immunogenic cell death (ICD), as dendritic cells (DCs) were found to engulf ICG-PDT-treated tumor cells and undergo phenotypic maturation. ICG accumulated in tumors 2 h after administration, as measured by fluorescence and photoacoustic imaging. Considering the advantages of ICG as a photosensitizer, we sought to design a therapy that combines PDT and immune checkpoint blockade to maximize tumor control. To this end, a 25% thermosensitive polymer 407 hydrogel was included as a co-delivery platform for this treatment scheme. NIR-PDT under 808 nm irradiation in combination with cytotoxic T-lymphocyte-associated protein 4 (CTLA4)/programmed death-ligand 1 (PD-L1) checkpoint blockade prolonged survival rate of colorectal tumor-bearing mice by inducing a series of immune responses, like the phagocytosis of tumor debris by macrophages and DCs, and induction of acute inflammation, leukocyte infiltration, maturation and activation of DCs. Altogether, our work presents a NIR-triggered PDT strategy in combination with immune checkpoint blockade. Compared to a single treatment, the combination treatment increased efficiency to inhibit solid tumor growth and improved the survival rate of tumor-bearing mice.
光动力疗法（PDT）通过产生活性氧（ROS）和诱导免疫反应，对各种类型的癌症显示出令人印象深刻的治疗效果。然而，在某些情况下，PDT诱导的免疫反应并不总是足以根除剩余的肿瘤细胞。另一方面，光敏剂吲哚菁绿（ICG）可以在近红外（NIR）光照下介导PDT，从而增加激发光进入肿瘤的穿透深度。我们发现ICG在体外能被结肠直肠癌MC38和CT26肿瘤细胞迅速摄取，并能促进PDT介导的细胞杀伤作用。我们的结果还表明，ICG可诱导免疫原性细胞死亡（ICD），因为发现树突状细胞（DCs）会吞噬经ICG-PDT处理的肿瘤细胞并发生表型成熟。给药后2小时，通过荧光和光声成像测量发现ICG在肿瘤中蓄积。考虑到ICG作为光敏剂的优势，我们试图设计一种将PDT与免疫检查点阻断相结合的疗法，以最大限度地控制肿瘤。为此，将25%的热敏聚合物407水凝胶作为这种治疗方案的共递送平台。808nm照射下的近红外光动力疗法（NIR-PDT）与细胞毒性T淋巴细胞相关蛋白4（CTLA4）/程序性死亡配体1（PD-L1）检查点阻断相结合，通过诱导一系列免疫反应，如巨噬细胞和DCs对肿瘤碎片的吞噬，以及诱导急性炎症、白细胞浸润、DCs的成熟和激活，延长了荷结肠直肠癌小鼠的存活率。总之，我们的工作提出了一种近红外触发的光动力疗法策略与免疫检查点阻断相结合的方法。与单一治疗相比，联合治疗提高了抑制实体瘤生长的效率，并提高了荷瘤小鼠的存活率。
