| Literature DB >> 35182481 |
Jia Z Shen1, Zhixin Qiu2, Qiulian Wu2, Guoxin Zhang3, Rebecca Harris4, Dahui Sun1, Juha Rantala5, William D Barshop6, Linjie Zhao2, Deguan Lv2, Kwang-Ai Won7, James Wohlschlegel6, Olle Sangfelt8, Heike Laman4, Jeremy N Rich9, Charles Spruck10.
Abstract
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 patients with cancer. 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.Entities:
Keywords: AXL; EYA2; FBXO7; FBXW7; GAS6; anti-PD-1 therapy; immune evasion; mesenchymal phenotype
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Year: 2022 PMID： 35182481 PMCID： PMC8934274 DOI： 10.1016/j.molcel.2022.01.022
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970