Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity.
Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity.
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用早期发生铁死亡的癌细胞进行疫苗接种可诱导有效的抗肿瘤免疫。
DOI：
10.1136/jitc-2020-001369
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发表时间：
2020-11
影响因子：
10.9
通讯作者：
Krysko DV
中科院分区：
文献类型：
--
作者：
Efimova I;Catanzaro E;Van der Meeren L;Turubanova VD;Hammad H;Mishchenko TA;Vedunova MV;Fimognari C;Bachert C;Coppieters F;Lefever S;Skirtach AG;Krysko O;Krysko DV
免疫疗法代表了临床癌症治疗的未来。癌细胞死亡的类型决定了抗肿瘤免疫反应，从而有助于抗癌治疗的疗效和患者的长期生存。癌细胞中免疫原性凋亡或坏死性凋亡的诱导确实会激活抗肿瘤免疫，但对这些细胞死亡方式的抵抗是常见的。因此，寻找其他杀死肿瘤细胞的方法具有重要意义。最近，铁死亡已被确定为一种新型的、铁依赖性调节细胞死亡形式，但铁死亡癌细胞是否具有免疫原性尚不清楚。 RAS选择性致死3诱导小鼠纤维肉瘤MCA205或神经胶质瘤GL261细胞中的铁死亡细胞死亡，并通过流式细胞术、原子力和共聚焦显微镜分析铁死亡。分别通过发光和 ELISA 检测检测 ATP 和高迁移率组盒 1 (HMGB1) 的释放。通过铁死亡癌细胞与骨髓源性树突状细胞 (BMDC) 共培养以及 BMDC 的吞噬和激活/成熟率（CD11c+CD86+、CD11c+CD40+、CD11c+MHCII+、IL-6、RNAseq 分析）来分析体外免疫原性。使用免疫功能正常和免疫受损（Rag-2−/−）小鼠的肿瘤预防性疫苗接种模型来分析铁死亡的免疫原性。共聚焦和原子力显微镜以及抑制剂分析证明，抑制谷胱甘肽过氧化物酶 4 可以在癌细胞中诱导铁死亡。我们首次证明铁死亡在体外和体内均具有免疫原性。早期而非晚期的铁死亡细胞促进 BMDC 表型成熟，并在免疫活性小鼠中引发疫苗样作用，但在 Rag-2−/− 小鼠中则不然，这表明免疫原性机制受到适应性免疫系统的严格调节，并且具有时间依赖性。此外，ATP 和 HMGB1 是参与免疫原性细胞死亡的最典型的损伤相关分子模式，已被证明沿着铁死亡的时间线被动释放，并充当与早期铁死亡癌细胞的免疫原性相关的免疫原性信号。这些结果为基于诱导铁死亡的癌症新治疗策略的开发铺平了道路，从而拓宽了当前免疫原性细胞死亡的概念，并为癌症免疫治疗新策略的开发打开了大门。
Immunotherapy represents the future of clinical cancer treatment. The type of cancer cell death determines the antitumor immune response and thereby contributes to the efficacy of anticancer therapy and long-term survival of patients. Induction of immunogenic apoptosis or necroptosis in cancer cells does activate antitumor immunity, but resistance to these cell death modalities is common. Therefore, it is of great importance to find other ways to kill tumor cells. Recently, ferroptosis has been identified as a novel, iron-dependent form of regulated cell death but whether ferroptotic cancer cells are immunogenic is unknown. Ferroptotic cell death in murine fibrosarcoma MCA205 or glioma GL261 cells was induced by RAS-selective lethal 3 and ferroptosis was analyzed by flow cytometry, atomic force and confocal microscopy. ATP and high-mobility group box 1 (HMGB1) release were detected by luminescence and ELISA assays, respectively. Immunogenicity in vitro was analyzed by coculturing of ferroptotic cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and activation/maturation of BMDCs (CD11c+CD86+, CD11c+CD40+, CD11c+MHCII+, IL-6, RNAseq analysis). The tumor prophylactic vaccination model in immune-competent and immune compromised (Rag-2−/−) mice was used to analyze ferroptosis immunogenicity. Ferroptosis can be induced in cancer cells by inhibition of glutathione peroxidase 4, as evidenced by confocal and atomic force microscopy and inhibitors’ analysis. We demonstrate for the first time that ferroptosis is immunogenic in vitro and in vivo. Early, but not late, ferroptotic cells promote the phenotypic maturation of BMDCs and elicit a vaccination-like effect in immune-competent mice but not in Rag-2−/− mice, suggesting that the mechanism of immunogenicity is very tightly regulated by the adaptive immune system and is time dependent. Also, ATP and HMGB1, the best-characterized damage-associated molecular patterns involved in immunogenic cell death, have proven to be passively released along the timeline of ferroptosis and act as immunogenic signal associated with the immunogenicity of early ferroptotic cancer cells. These results pave the way for the development of new therapeutic strategies for cancers based on induction of ferroptosis, and thus broadens the current concept of immunogenic cell death and opens the door for the development of new strategies in cancer immunotherapy.
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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
DOI：
10.1084/jem.20050915
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casares N;Pequignot MO;Tesniere A;Ghiringhelli F;Roux S;Chaput N;Schmitt E;Hamai A;Hervas-Stubbs S;Obeid M;Coutant F;Métivier D;Pichard E;Aucouturier P;Pierron G;Garrido C;Zitvogel L;Kroemer G
通讯作者：
Kroemer G
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：
7.3
作者：
Garg AD;Galluzzi L;Apetoh L;Baert T;Birge RB;Bravo-San Pedro JM;Breckpot K;Brough D;Chaurio R;Cirone M;Coosemans A;Coulie PG;De Ruysscher D;Dini L;de Witte P;Dudek-Peric AM;Faggioni A;Fucikova J;Gaipl US;Golab J;Gougeon ML;Hamblin MR;Hemminki A;Herrmann M;Hodge JW;Kepp O;Kroemer G;Krysko DV;Land WG;Madeo F;Manfredi AA;Mattarollo SR;Maueroder C;Merendino N;Multhoff G;Pabst T;Ricci JE;Riganti C;Romano E;Rufo N;Smyth MJ;Sonnemann J;Spisek R;Stagg J;Vacchelli E;Vandenabeele P;Vandenberk L;Van den Eynde BJ;Van Gool S;Velotti F;Zitvogel L;Agostinis P
通讯作者：
Agostinis P
影响因子：
9
作者：
Huang, C-Y;Kuo, W-T;Huang, Y-C;Lee, T-C;Yu, L. C. H.
通讯作者：
Yu, L. C. H.