Study of ultrastructural changes in cell treated with cytotoxic compounds inducing immunogenic cell death

This proposal takes advantage of high-resolution imaging technologies to identify molecular patterns generated during immunogenic cell death (ICD) in tumour cells. ICD is a recently described, poorly understood process involving regulated tumour cell death as a signal for immune responses. We aim to use state-of-the-art cryocorrelative soft-X-ray tomography to allow tracking changes in metabolic organelles relevant to tumour cell biology, such as mitochondria and lipid droplets, upon treatment with chemotherapeutic compounds leading to ICD and non-ICD. As a complementary approach, we plan to use organometallic platinum compounds to identify their location in cells and to correlate it with morphological changes in these specific organelles. This 3D elemental imaging, if successful, combined with the analysis of the ultrastructural changes, can serve to infer the mechanism of action of the different compounds. The discovery of structural patterns in organelles would be used as features to identify potential ICD-promoting compounds to treat cancer. These patterns are potentially useful to identify bioactive elements that enhance immunogenicity, key to the development of effective combination therapies against cancer.

本研究提案依托高分辨成像技术，旨在识别肿瘤细胞在免疫原性细胞死亡（immunogenic cell death, ICD）过程中产生的分子模式。免疫原性细胞死亡是近年才被报道、目前尚缺乏系统研究的过程，其以受调控的肿瘤细胞死亡作为触发免疫应答的信号。本研究拟采用当前最先进的低温关联软X射线断层成像技术，追踪经可诱导免疫原性细胞死亡与非免疫原性细胞死亡的化疗化合物处理后，与肿瘤细胞生物学功能密切相关的代谢细胞器（如线粒体与脂滴）的动态变化。作为补充研究策略，我们计划使用有机金属铂化合物，定位其在细胞内的分布位置，并将其与上述特定细胞器的形态变化进行关联分析。此项三维元素成像技术若能成功实现，结合超微结构变化分析，可用于推断不同受试化合物的作用机制。本研究中发现的细胞器结构模式，将作为特征标签用于筛选潜在的免疫原性细胞死亡诱导化合物，以用于癌症治疗。这些结构模式还有望用于识别可增强免疫原性的生物活性成分，而这正是开发高效癌症联合疗法的核心关键。