Abstract
Immunogenic cell death significantly contributes to the success of anti-cancer therapies, but immunogenicity of different cell death modalities widely varies. Ferroptosis, a form of cell death that is characterized by iron accumulation and lipid peroxidation, has not yet been fully evaluated from this perspective. Here we present an inducible model of ferroptosis, distinguishing three phases in the process-'initial' associated with lipid peroxidation, 'intermediate' correlated with ATP release and 'terminal' recognized by HMGB1 release and loss of plasma membrane integrity-that serves as tool to study immune cell responses to ferroptotic cancer cells. Co-culturing ferroptotic cancer cells with dendritic cells (DC), reveals that 'initial' ferroptotic cells decrease maturation of DC, are poorly engulfed, and dampen antigen cross-presentation. DC loaded with ferroptotic, in contrast to necroptotic, cancer cells fail to protect against tumor growth. Adding ferroptotic cancer cells to immunogenic apoptotic cells dramatically reduces their prophylactic vaccination potential. Our study thus shows that ferroptosis negatively impacts antigen presenting cells and hence the adaptive immune response, which might hinder therapeutic applications of ferroptosis induction.
摘要
免疫性细胞死亡极大地促进了抗癌疗法的成功，但不同细胞死亡方式的免疫原性差异很大。铁死亡是一种以铁积累和脂质过氧化为特征的细胞死亡形式，目前尚未从肿瘤免疫角度进行全面研究。在这项研究中，我们提出了一个可诱导的铁死亡模型，区分了过程中的三个阶段--与脂质过氧化相关的 "初始阶段"、与ATP释放相关的 "中间阶段 "以及与HMGB1释放和质膜完整性丧失相关的 "终端阶段"，作为研究免疫细胞对铁死亡的癌细胞反应的工具。将铁死亡的癌细胞与树突状细胞（DC）共同培养，发现 "初始 "铁死亡的细胞降低了DC的成熟，吞噬能力降低，并抑制了抗原交叉呈现。与发生铁死亡的癌细胞相反，装载了铁死亡癌细胞的DC不能保护肿瘤的生长。将发生铁死亡的癌细胞加入到免疫性凋亡细胞中，极大地降低了它们的预防性疫苗接种潜力。因此，我们的研究表明，铁死亡会对抗原呈递细胞产生负面影响，从而影响适应性免疫反应，这可能阻碍铁死亡诱导治疗的应用。
参考文献
Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity. Nature communications, 2022, 13(1), 3676. doi: 10.1038/s 41467-022-31218-2.
