838 ETV6 rearrangements impair T cell infiltration via activating β-Catenin signaling in triple-negative breast cancer
Year: 2026
Type: conference-abstract
Abstract: Background Triple-negative breast cancer (TNBC) remains the most lethal subtype due to a lack of targets and profound chemotherapy resistance. Even with immune checkpoint blockade (ICB), the benefit remains minimal, with response rates as low as 5-10% for monotherapy and only a 12-13.6% gain when combined with chemotherapy, highlighting a critical need to identify genetic drivers of immune evasion.Methods In this study, we identified ETV6 structural rearrangements including gene fusions and exon duplications or deletions in ~13% of TNBC, enriched in ~35% of the aggressive mesenchymal subtype. These ETV6-rearranged tumors are immunologically ‘cold,’ with profound T-cell exclusion and suppressed interferon-γ signatures. Mechanistically, the variants act as dominant-negatives of wild-type ETV6, activate β-catenin signaling, and suppress NF-κB inflammatory responses. This dual mechanism drives an immunosuppressive microenvironment and impairs T-cell trafficking. Conversely, restoring wtETV6 expression significantly enhanced human T-cell infiltration in a paired bilateral humanized mouse model. Genetic knockdown of an endogenous ETV6 exon duplication restores NF-κB and interferon responses. Furthermore, pharmacological Wnt/β-catenin inhibition reversed immune suppression and significantly enhanced CD8 + T-cell recruitment.Results Mechanistically, the variants act as dominant-negatives of wild-type ETV6, activate β-catenin signaling, and suppress NF-κB inflammatory responses. This dual mechanism drives an immunosuppressive microenvironment and impairs T-cell trafficking. Conversely, restoring wtETV6 expression significantly enhanced human T-cell infiltration in a paired bilateral humanized mouse model. Genetic knockdown of an endogenous ETV6 exon duplication restores NF-κB and interferon responses. Furthermore, pharmacological Wnt/β-catenin inhibition reversed immune suppression and significantly enhanced CD8 + T-cell recruitment.Conclusions These findings establish ETV6 rearrangements as novel, actionable drivers of immune evasion and biomarkers for stratifying TNBC patients for Wnt/β-catenin-targeted therapies to overcome ICB resistance.
Authors: Xiaosong Wang, Yue Wang, Binfeng Lu
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225139801