Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer.
Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer.
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DOI：
10.1016/j.isci.2023.108308
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发表时间：
2023-12-15
期刊：
影响因子：
5.8
通讯作者：
Chadli, Ahmed
中科院分区：
文献类型：
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作者：
Eisa, Nada H.;Crowley, Vincent M.;Elahi, Asif;Kommalapati, Vamsi Krishna;Serwetnyk, Michael A.;Llbiyi, Taoufik;Lu, Sumin;Kainth, Kashish;Jilani, Yasmeen;Marasco, Daniela;El Andaloussi, Abdeljabar;Lee, Sukyeong;Tsai, Francis T. F.;Rodriguez, Paulo C.;Munn, David;Celis, Esteban;Korkaya, Hasan;Debbab, Abdessamad;Blagg, Brian;Chadli, Ahmed
低反应率和免疫相关不良事件限制了癌症免疫疗法的显着影响。为了改善临床结果，临床前研究表明，将免疫疗法与 N 端 Hsp90 抑制剂相结合可提高疗效，尽管诱导广泛的热休克反应 (HSR) 和这些抑制剂的低于最佳剂量限制了其作为单一疗法的临床疗效。我们发现天然产物 Enniatin A (EnnA) 以 Hsp90 为靶点，并破坏其客户癌蛋白的稳定性，而不诱导 HSR。 EnnA 在三阴性乳腺癌 (TNBC) 同基因小鼠模型中触发免疫原性细胞死亡，并且与 Hsp90 N 末端抑制剂相比表现出优异的抗肿瘤活性。 EnnA 重新编程肿瘤微环境 (TME)，通过降低 PD-L1 水平和激活趋化因子受体 CX3CR1 通路来促进 CD8+ T 细胞依赖性抗肿瘤免疫。这些发现为通过将 Hsp90 与涉及新作用机制的治疗剂结合来将免疫抑制性 TME 转变为对肿瘤更具敌意的环境提供了强有力的证据。 Enniatin A 靶向分子伴侣 Hsp90，而不诱导热休克反应 Enniatin A 在侵袭性 TNBC 模型中诱导免疫原性细胞死亡 Enniatin A 通过减少 PD-L1 蛋白和激活 CX3CR1 来减少免疫抑制 Enniatin A 促进 CD8+ T 细胞介导的针对 TNBC 微环境的抗肿瘤免疫；生物科学；分子生物学；癌症
Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8+ T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action. Enniatin A targets the chaperone Hsp90 without inducing a heat shock response Enniatin A induces immunogenic cell death in aggressive TNBC models Enniatin A reduces immunosuppression by reducing PD-L1 protein and activating CX3CR1 Enniatin A promotes CD8+ T cell-mediated anti-tumor immunity against TNBC Microenvironment; Biological sciences; Molecular biology; Cancer
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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：
8.8
作者：
Jenkins RW;Barbie DA;Flaherty KT
通讯作者：
Flaherty KT
影响因子：
64.5
作者：
Dai, Chengkai;Whitesell, Luke;Lindquist, Susan
通讯作者：
Lindquist, Susan
影响因子：
5.2
作者：
Dornetshuber, Rita;Heffeter, Petra;Berger, Walter
通讯作者：
Berger, Walter
影响因子：
64.8
作者：
Herbst RS;Soria JC;Kowanetz M;Fine GD;Hamid O;Gordon MS;Sosman JA;McDermott DF;Powderly JD;Gettinger SN;Kohrt HE;Horn L;Lawrence DP;Rost S;Leabman M;Xiao Y;Mokatrin A;Koeppen H;Hegde PS;Mellman I;Chen DS;Hodi FS
通讯作者：
Hodi FS