A FBXO7/EYA2-SCF(FBXW7) axis promotes AXL-mediated maintenance of mesenchymal and immune evasion phenotypes of cancer cells.
A FBXO7/EYA2-SCF(FBXW7) axis promotes AXL-mediated maintenance of mesenchymal and immune evasion phenotypes of cancer cells.
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一个FBXO7/EYA2 - SCF(FBXW7)轴促进AXL介导的癌细胞间充质和免疫逃逸表型的维持。
DOI：
10.1016/j.molcel.2022.01.022
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发表时间：
2022-03-17
期刊：
影响因子：
16
通讯作者：
Spruck C
中科院分区：
文献类型：
--
作者：
Shen JZ;Qiu Z;Wu Q;Zhang G;Harris R;Sun D;Rantala J;Barshop WD;Zhao L;Lv D;Won KA;Wohlschlegel J;Sangfelt O;Laman H;Rich JN;Spruck C
间充质肿瘤表型与免疫治疗耐药相关，尽管其机制尚不清楚。在此，我们确定FBXO7是癌细胞间充质和免疫逃逸表型的维持调节因子。FBXO7结合并稳定SIX1共转录调节因子EYA2，刺激间充质基因表达，抑制由AXL细胞外配体GAS6驱动的IFNα/β、趋化因子CXCL9/10和抗原呈递机制。泛素连接酶SCF^{FBXW7}通过促进EYA2降解来拮抗这一通路。靶向EYA2酪氨酸磷酸酶活性可降低间充质表型并增强癌细胞的免疫原性，从而导致肿瘤生长和转移减弱，细胞毒性T细胞和NK细胞浸润增加，并在小鼠肿瘤模型中增强抗PD - 1治疗反应。FBXO7的表达与癌症患者的间充质和免疫抑制特征相关。一种FBXO7 - 免疫基因特征可预测免疫治疗反应。总之，FBXO7/EYA2 - SCF^{FBXW7}轴维持癌细胞的间充质和免疫逃逸表型，为评估FBXO7/EYA2抑制剂与免疫疗法联合使用以增强肿瘤免疫治疗反应提供了理论依据。
在本文中，Shen等人确定了一种新的调节通路FBXO7/EYA2 - SCF^{FBXW7}，它通过刺激GAS6 - AXL信号传导来维持癌细胞的间充质和免疫逃逸表型。靶向FBXO7/EYA2可降低间充质表型和癌症干细胞，并增强免疫原性，从而产生独立的抗肿瘤活性并增强免疫治疗反应。
A mesenchymal tumor phenotype associates with immunotherapy resistance, although the mechanism is unclear. Here, we identified FBXO7 as a maintenance regulator of mesenchymal and immune evasion phenotypes of cancer cells. FBXO7 bound and stabilized SIX1 co-transcriptional regulator EYA2, stimulating mesenchymal gene expression and suppressing IFNα/β, chemokines CXCL9/10, and antigen presentation machinery, driven by AXL extracellular ligand GAS6. Ubiquitin ligase SCFFBXW7 antagonized this pathway by promoting EYA2 degradation. Targeting EYA2 Tyr phosphatase activity decreased mesenchymal phenotypes and enhanced cancer cell immunogenicity, resulting in attenuated tumor growth and metastasis, increased infiltration of cytotoxic T and NK cells, and enhanced anti-PD-1 therapy response in mouse tumor models. FBXO7 expression correlated with mesenchymal and immune-suppressive signatures in cancer patients. An FBXO7-immune gene signature predicted immunotherapy responses. Collectively, the FBXO7/EYA2-SCFFBXW7 axis maintains mesenchymal and immune evasion phenotypes of cancer cells, providing rationale to evaluate FBXO7/EYA2 inhibitors in combination with immune-based therapies to enhance onco-immunotherapy responses. In this article, Shen et al. identify a novel regulatory pathway, FBXO7/EYA2-SCFFBXW7, that maintains mesenchymal and immune evasion phenotypes of cancer cells by stimulating GAS6-AXL signaling. Targeting FBXO7/EYA2 decreased mesenchymal phenotypes and cancer stem cells and enhanced immunogenicity, leading to stand-alone antitumor activity and augmented immunotherapy response.
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影响因子：
4.8
作者：
Krueger, Aaron B.;Drasin, David J.;Zhao, Rui
通讯作者：
Zhao, Rui
影响因子：
28.2
作者：
Gstalder C;Liu D;Miao D;Lutterbach B;DeVine AL;Lin C;Shettigar M;Pancholi P;Buchbinder EI;Carter SL;Manos MP;Rojas-Rudilla V;Brennick R;Gjini E;Chen PH;Lako A;Rodig S;Yoon CH;Freeman GJ;Barbie DA;Hodi FS;Miles W;Van Allen EM;Haq R
通讯作者：
Haq R
影响因子：
4.4
作者：
Geis-Asteggiante L;Belew AT;Clements VK;Edwards NJ;Ostrand-Rosenberg S;El-Sayed NM;Fenselau C
通讯作者：
Fenselau C
通过辐射和靶向AXL重新编程免疫学微环境。
影响因子：
16.6
作者：
通讯作者：
--
DOI：
10.1073/pnas.0909333107
发表时间：
2010-01-19
影响因子：
11.1
作者：
Gjerdrum, Christine;Tiron, Crina;Lorens, James B.
通讯作者：
Lorens, James B.