TWIST1 Drives Cytotoxic CD8+ T-Cell Exhaustion through Transcriptional Activation of CD274 (PD-L1) Expression in Breast Cancer Cells

Authors

Xiaobin Yu
Jianming Xu

Publication Date

5-22-2024

Journal

Cancers

DOI

10.3390/cancers16111973

PMID

38893094

PMCID

PMC11171171

PubMedCentral® Posted Date

5-22-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

breast cancer, TWIST1, EMT, metastasis, immunosuppression, PD-L1, immune-checkpoint-inhibitor therapy

Abstract

In breast cancer, epithelial-mesenchymal transition (EMT) is positively associated with programmed death ligand 1 (PD-L1) expression and immune escape, and TWIST1 silences ERα expression and induces EMT and cancer metastasis. However, how TWIST1 regulates PD-L1 and immune evasion is unknown. This study analyzed TWIST1 and PD-L1 expression in breast cancers, investigated the mechanism for TWIST1 to regulate PD-L1 transcription, and assessed the effects of TWIST1 and PD-L1 in cancer cells on cytotoxic CD8+ T cells. Interestingly, TWIST1 expression is correlated with high-level PD-L1 expression in ERα-negative breast cancer cells. The overexpression and knockdown of TWIST1 robustly upregulate and downregulate PD-L1 expression, respectively. TWIST1 binds to the PD-L1 promoter and recruits the TIP60 acetyltransferase complex in a BRD8-dependent manner to transcriptionally activate PD-L1 expression, which significantly accelerates the exhaustion and death of the cytotoxic CD8+ T cells. Accordingly, knockdown of TWIST1 or BRD8 or inhibition of PD-L1 significantly enhances the tumor antigen-specific CD8+ T cells to suppress the growth of breast cancer cells. These results demonstrate that TWIST1 directly induces PD-L1 expression in ERα-negative breast cancer cells to promote immune evasion. Targeting TWIST1, BRD8, and/or PD-L1 in ERα-negative breast cancer cells with TWIST1 expression may sensitize CD8+ T-cell-mediated immunotherapy.

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