背景:化学免疫疗法,这得益于化疗和免疫疗法的结合,已经成为癌症治疗中一种有前途的策略。然而,有效诱导强健的免疫应答仍然具有挑战性,因为患者之间的应答能力有限.内质网(ER)应激对于激活与免疫原性细胞死亡(ICD)相关的细胞内信号通路至关重要。针对ER的靶向药物可能会增强ER应激并改善ICD相关的免疫治疗.
目的:提高化疗免疫疗法的免疫应答。
方法:构建ER靶向纳米颗粒TSE-CEL/NP以增强免疫原性癌细胞死亡。流式细胞术,共聚焦显微镜,TEM和免疫荧光用于评估ER靶向作用和免疫原性肿瘤细胞对B16F10肿瘤细胞的体外死亡。构建单侧和双侧肿瘤模型以研究体内抗肿瘤和免疫疗法的功效。肺转移B16F10黑素瘤荷瘤小鼠用于评估抗转移功效。
结果:TSE-CEL/NP可以在ER中特别积累,从而引起ER应激。高ER应力触发CRT的暴露,HMGB1和ATP的胞外释放。这些危险信号随后促进树突状细胞(DC)的募集和成熟,这反过来又增加了细胞毒性T淋巴细胞(CD8+T细胞)的增殖,最终改善了针对黑色素瘤的免疫疗法疗效.体内实验表明TSE-CEL/NP表现出优异的抗肿瘤功效并引发强烈的免疫应答。
结论:我们的发现为黑色素瘤免疫治疗提供了新的ER靶向方法和实验基础。
BACKGROUND: Chemoimmunotherapy, which benefits from the combination of chemotherapy and immunotherapy, has emerged as a promising strategy in cancer treatment. However, effectively inducing a robust immune response remains challenging due to the limited responsiveness across patients. Endoplasmic reticulum (ER) stress is essential for activating intracellular signaling pathways associated with immunogenic cell death (ICD), targeting drugs to ER might enhance ER stress and improve ICD-related immunotherapy.
OBJECTIVE: To improve the immune response of Chemoimmunotherapy.
METHODS: ER targeting nanoparticles TSE-CEL/NP were constructed to enhance immunogenic cancer cell death. Flow cytometry, confocal microscope, TEM and immunofluorescence were used to evaluate the ER targeting effect and immunogenic tumor cell death in vitro on B16F10 tumor cells. Unilateral and bilateral tumor models were constructed to investigate the efficacy of anti-tumor and immunotherapy in vivo. Lung metastasis B16F10 melanoma tumor-bearing mice were used to assess the anti-metastasis efficacy.
RESULTS: TSE-CEL/NP could specially accumulate in ER, thereby induce ER stress. High ER stress trigger the exposure of CRT, the extracellular release of HMGB1 and ATP. These danger signals subsequently promote the recruitment and maturation of dendritic cells (DCs), which in turn increase the proliferation of cytotoxic T lymphocytes (CD8+ T cells), ultimately resulted in an improved immunotherapy efficacy against melanoma. Invivo experiments showed that TSE-CEL/NP exhibits excellent antitumor efficacy and triggers a strong immune response.
CONCLUSIONS: Our findings demonstrated that celastrol ER targeting delivery could amplify immunogenic cell death in melanoma, which provide experimental basis for melanoma immunotherapy.