Department of Medicine, Penn State College of Medicine, Hershey, PA, USA.
Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA.
Oncoimmunology. 2022 Aug 3;11(1):2104551. doi: 10.1080/2162402X.2022.2104551. eCollection 2022.
Our previous study showed that one of the schweinfurthin compounds, 5'-methoxyschweinfurthin G (MeSG), not only enhances the anti-tumor effect of anti-PD1 antibody in the B16F10 murine melanoma model, but also provokes durable, protective anti-tumor immunity. Here we further investigated the mechanisms by which MeSG treatment induces immunogenic cell death (ICD). MeSG induced significant cell surface calreticulin (CRT) exposure in a time and concentration dependent manner as well as increased phagocytosis of tumor cells by dendritic cells in vitro. Interestingly, this CRT exposure differs from the canonical pathway in several aspects. MeSG does not cause ER stress and does not require PERK to induce CRT exposure. Caspase inhibitors partially rescue cells from MeSG-induced apoptosis, but fail to reduce CRT exposure. MeSG does not cause ERp57 exposure and the absence of ERp57 expression does not reduce CRT exposure. Finally, an intact ER to Golgi transport system is required for this phenomenon. These results lend support to the development of the schweinfurthin family as drugs to enhance clinical response to immunotherapy and highlight the need for additional research on the mechanisms of ICD induction.
我们之前的研究表明，一种来源于 Schweinfurthia 属植物的化合物 5'-甲氧基 Schweinfurthin G（MeSG）不仅增强了 B16F10 黑色素瘤模型中抗 PD-1 抗体的抗肿瘤作用，而且还引发了持久的保护性抗肿瘤免疫。在此，我们进一步研究了 MeSG 治疗诱导免疫原性细胞死亡（ICD）的机制。MeSG 以时间和浓度依赖的方式诱导显著的细胞表面钙网蛋白（CRT）暴露，并增加树突状细胞体外对肿瘤细胞的吞噬作用。有趣的是，这种 CRT 暴露在几个方面与经典途径不同。MeSG 不会引起内质网应激，也不需要 PERK 诱导 CRT 暴露。半胱天冬酶抑制剂部分挽救 MeSG 诱导的细胞凋亡，但不能减少 CRT 暴露。MeSG 不会引起 ERp57 暴露，并且 ERp57 表达缺失不会减少 CRT 暴露。最后，需要完整的内质网到高尔基体运输系统来实现这一现象。这些结果为 Schweinfurthia 属植物化合物的开发提供了支持，以增强对免疫疗法的临床反应，并强调需要进一步研究 ICD 诱导的机制。
