背景:免疫监视对抗癌治疗和肿瘤控制的有效性至关重要。顺铂在激活免疫监视方面的无效归因于其缺乏佐剂性,这是由于其无法刺激内质网应激所致。双氢青蒿素通过多种机制发挥抗肿瘤作用,包括内质网应激的激活。本研究旨在开发一种新的策略,通过联合使用顺铂和双氢青蒿素来增强垂死肿瘤细胞的免疫原性。从而引发有效的抗肿瘤免疫监视,提高顺铂在临床实践中的疗效。
方法:本研究使用Lewis肺癌(LLC)和CT26结肠癌细胞系和皮下肿瘤模型。免疫监视的重要性在免疫活性和免疫缺陷小鼠模型中都得到了验证。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肿瘤生长控制的能力。通过PERK/eIF2α途径在体外和体内的药物或遗传干预阐明了潜在的机制。
结果:双氢青蒿素增强了顺铂处理的LLC和CT26癌细胞中活性氧的产生。双氢青蒿素与顺铂的联合治疗可促进细胞死亡,并确保从垂死的癌细胞中最佳释放与损伤相关的分子模式。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联合顺铂治疗可诱导免疫原性细胞死亡。利用免疫活性和免疫缺陷小鼠模型,我们进一步证明,联合治疗抑制CT26结肠癌和LLC肺癌的肿瘤生长,通过恢复细胞毒性T淋巴细胞反应和体内抗癌免疫监视的恢复,从而改善预后。机械上,双氢青蒿素通过激活损伤相关分子模式的佐剂来恢复顺铂的免疫原性,如钙网蛋白暴露,通过PERK/eIF2α途径。此外,eIF2α磷酸化的抑制减弱了体内C+D的抗肿瘤效率。
结论:我们强调双氢青蒿素作为顺铂的免疫原性细胞死亡救助者,以PERK/eIF2α依赖性方式激活抗癌免疫监视,并提供在临床实践中增强顺铂抗肿瘤功效的策略。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.