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.
在乳腺癌中，上皮-间质转化（EMT）与程序性死亡配体1（PD-L1）表达及免疫逃逸呈正相关，而TWIST1通过沉默ERα表达诱导EMT及癌症转移。然而，TWIST1如何调控PD-L1及免疫逃逸机制尚未明确。本研究通过分析乳腺癌中TWIST1与PD-L1的表达模式，探究TWIST1调控PD-L1转录的分子机制，并评估癌细胞中TWIST1与PD-L1对细胞毒性CD8+ T细胞的影响。值得注意的是，在ERα阴性乳腺癌细胞中，TWIST1表达与高水平PD-L1表达显著相关。TWIST1的过表达与敲低分别能强力上调和下调PD-L1表达。机制上，TWIST1结合于PD-L1启动子区域，并以BRD8依赖性方式募集TIP60乙酰转移酶复合体，从而转录激活PD-L1表达，显著加速细胞毒性CD8+ T细胞的耗竭与死亡。相应地，敲低TWIST1或BRD8，或抑制PD-L1功能，可显著增强肿瘤抗原特异性CD8+ T细胞对乳腺癌细胞生长的抑制作用。这些结果表明，TWIST1能直接诱导ERα阴性乳腺癌细胞中PD-L1表达以促进免疫逃逸。针对表达TWIST1的ERα阴性乳腺癌细胞中TWIST1、BRD8和/或PD-L1的靶向干预，可能增强CD8+ T细胞介导的免疫治疗效果。
肿瘤(癌症)患者之家