Li Yumei, Ma Pei, Li Jingxia, Wu Feng, Guo Mengfei, Zhou E, Song Siwei, Wang Sufei, Zhang Shuai, Jin Yang
Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Pulmonary Diseases of National Health Commission, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
The Ministry of Education Key Laboratory of Biological Targeted Therapy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
Cell Biosci. 2024 Aug 1;14(1):100. doi: 10.1186/s13578-024-01254-0.
Immunosurveillance is pivotal in the effectiveness of anticancer therapies and tumor control. The ineffectiveness of cisplatin in activating the immunosurveillance is attributed to its lack of adjuvanticity resulting from its inability to stimulate endoplasmic reticulum stress. Dihydroartemisinin demonstrates the anti-tumor effects through various mechanisms, including the activation of the endoplasmic reticulum stress. This study aimed to develop a novel strategy to enhance the immunogenicity of dying tumor cells by combining cisplatin with dihydroartemisinin, thereby triggering effective anti-tumor immunosurveillance and improving the efficacy of cisplatin in clinical practice.
Lewis lung carcinoma (LLC) and CT26 colon cancer cell lines and subcutaneous tumor models were used in this study. The importance of immunosurveillance was validated in both immunocompetent and immunodeficient mouse models. The ability of dihydroartemisinin and cisplatin therapy to induce immunogenic cell death and tumor growth control in vivo was validated by prophylactic tumor vaccination and therapeutic tumor models. The underlying mechanism was elucidated through the pharmaceutical or genetic intervention of the PERK/eIF2α pathway in vitro and in vivo.
Dihydroartemisinin enhanced the generation of reactive oxygen species in cisplatin-treated LLC and CT26 cancer cells. The combination treatment of dihydroartemisinin with cisplatin promoted cell death and ensured an optimal release of damage-associated molecular patterns from dying cancer cells, promoting the phagocytosis of dendritic cells. In the tumor vaccination model, we confirmed that dihydroartemisinin plus cisplatin treatment induced immunogenic cell death. Utilizing immunocompetent and immunodeficient mouse models, we further demonstrated that the combination treatment suppressed the tumor growth of CT26 colon cancer and LLC lung cancer, leading to an improved prognosis through the restoration of cytotoxic T lymphocyte responses and reinstatement of anti-cancer immunosurveillance in vivo. Mechanistically, dihydroartemisinin restored the immunogenicity of cisplatin by activating the adjuvanticity of damage-associated molecular patterns, such as calreticulin exposure, through the PERK/eIF2α pathway. Additionally, the inhibition of eIF2α phosphorylation attenuated the anti-tumor efficiency of C + D in vivo.
We highlighted that dihydroartemisinin acts as an immunogenic cell death rescuer for cisplatin, activating anticancer immunosurveillance in a PERK/eIF2α-dependent manner and offering a strategy to enhance the anti-tumor efficacy of cisplatin in clinical practice.
免疫监视在抗癌治疗的有效性和肿瘤控制中起着关键作用。顺铂激活免疫监视无效归因于其缺乏佐剂活性，这是由于它无法刺激内质网应激。双氢青蒿素通过多种机制发挥抗肿瘤作用，包括激活内质网应激。本研究旨在开发一种新策略，通过将顺铂与双氢青蒿素联合使用来增强垂死肿瘤细胞的免疫原性，从而触发有效的抗肿瘤免疫监视并提高顺铂在临床实践中的疗效。
本研究使用了Lewis肺癌（LLC）和CT26结肠癌细胞系以及皮下肿瘤模型。在免疫健全和免疫缺陷小鼠模型中验证了免疫监视的重要性。通过预防性肿瘤疫苗接种和治疗性肿瘤模型验证了双氢青蒿素和顺铂治疗在体内诱导免疫原性细胞死亡和控制肿瘤生长的能力。通过体外和体内对PERK/eIF2α通路的药物或基因干预阐明潜在机制。
双氢青蒿素增强了顺铂处理的LLC和CT26癌细胞中活性氧的生成。双氢青蒿素与顺铂联合治疗促进细胞死亡，并确保垂死癌细胞中损伤相关分子模式的最佳释放，促进树突状细胞的吞噬作用。在肿瘤疫苗接种模型中，我们证实双氢青蒿素加顺铂治疗诱导了免疫原性细胞死亡。利用免疫健全和免疫缺陷小鼠模型，我们进一步证明联合治疗抑制了CT26结肠癌和LLC肺癌的肿瘤生长，通过恢复细胞毒性T淋巴细胞反应和在体内恢复抗癌免疫监视改善了预后。机制上，双氢青蒿素通过PERK/eIF2α通路激活损伤相关分子模式（如钙网蛋白暴露）的佐剂活性，从而恢复顺铂的免疫原性。此外，抑制eIF2α磷酸化减弱了体内C+D的抗肿瘤效率。
我们强调双氢青蒿素作为顺铂的免疫原性细胞死亡拯救剂，以PERK/eIF2α依赖的方式激活抗癌免疫监视，并为提高顺铂在临床实践中的抗肿瘤疗效提供了一种策略。
