Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity.
Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity.
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DOI：
10.1038/s41467-022-31218-2
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发表时间：
2022-06-27
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
免疫原性细胞死亡显著有助于抗癌疗法的成功，但不同细胞死亡方式的免疫原性差异很大。铁凋亡是一种以铁积累和脂质过氧化为特征的细胞死亡形式，尚未从这一角度进行充分评估。在这里，我们提出了一个诱导型铁凋亡模型，区分三个阶段的过程中-“初始”与脂质过氧化，“中间”与ATP的释放和“终端”识别的HMGB 1释放和质膜完整性的损失，作为工具来研究免疫细胞反应的铁凋亡癌细胞。共培养铁凋亡癌细胞与树突状细胞（DC），揭示了“初始”铁凋亡细胞减少DC的成熟，被吞噬不良，并抑制抗原交叉呈递。与坏死性凋亡癌细胞相反，负载铁凋亡癌细胞的DC不能防止肿瘤生长。在免疫原性凋亡细胞中加入铁凋亡癌细胞显著降低了它们的预防性疫苗接种潜力。因此，我们的研究表明，铁凋亡对抗原呈递细胞产生负面影响，从而影响适应性免疫应答，这可能会阻碍铁凋亡诱导的治疗应用。诱导肿瘤细胞的铁凋亡是一种有前途的癌症治疗方法。作者在此表明，另一方面，通过铁凋亡死亡的细胞比坏死性凋亡细胞的免疫原性低，它们抑制树突状细胞的成熟和抗原交叉呈递，从而降低抗肿瘤免疫应答。
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. Inducing ferroptosis of tumour cells is a promising therapeutic approach in cancer. Authors show here that on the other hand, cells dying via ferroptosis are less immunogenic than necroptotic cells, they inhibit maturation and antigen cross-presentation of dendritic cells, hence lessen the anti-tumour immune response.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
9
作者：
Adjemian S;Oltean T;Martens S;Wiernicki B;Goossens V;Vanden Berghe T;Cappe B;Ladik M;Riquet FB;Heyndrickx L;Bridelance J;Vuylsteke M;Vandecasteele K;Vandenabeele P
通讯作者：
Vandenabeele P
影响因子：
4.7
作者：
Chen J;Zhan Y;Zhang R;Chen B;Huang J;Li C;Zhang W;Wang Y;Gao Y;Zheng J;Li Y
通讯作者：
Li Y
影响因子：
4.4
作者：
Aaes, Tania Love;Verschuere, Hanne;Vandenabeele, Peter
通讯作者：
Vandenabeele, Peter
影响因子：
16.6
作者：
Feng, Mingye;Marjon, Kristopher D.;Weissman, Irving L.
通讯作者：
Weissman, Irving L.