miR-155 enhances PRC2 activity via polycomb-like protein Phf19 to sustain T cell antitumor immunity [ChIP-Seq]

The microRNA miR-155 is essential for CD8+ T cell antiviral and antitumor immunity but the mechanisms behind its activity remain unresolved. Here, we show that miR-155 increased CD8+ T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of key drivers of effector differentiation. miR-155 enhanced the function of polycomb repressor complex 2 (PRC2) indirectly by promoting the expression of the PRC2 cofactor Phf19 via AKT signaling. Phf19 orchestrated a transcriptional program extensively shared with miR-155 to enhance T cell engraftment, polyfunctionality, and antitumor immunity. These effects were dependent on the histone-binding capacity of Phf19 which is critical for the PRC2 recruitment to chromatin. These findings establish miR-155–Phf19–PRC2 as a pivotal axis regulating CD8+ T cell differentiation. Targeting the microRNA–polycomb-group protein circuitry is a promising route to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate. We compared the H3K27me3 binding profiles of Pmel-1 CD8+ T cells overexpressing with miR-155 or Controls 5 days after transduction.

微小RNA（microRNA）miR-155对于CD8阳性T细胞的抗病毒与抗肿瘤免疫至关重要，但其发挥功能的具体机制仍未明确。本研究显示，miR-155可通过表观遗传沉默效应细胞分化的关键调控因子，抑制T细胞衰老与功能耗竭，从而增强CD8阳性T细胞的抗肿瘤功能。miR-155可通过AKT信号通路促进多梳抑制复合体2（polycomb repressor complex 2，PRC2）的辅助因子Phf19的表达，间接增强PRC2的活性。Phf19可调控一套与miR-155高度共享的转录程序，以提升T细胞的植入能力、多功能性与抗肿瘤免疫活性。上述效应依赖于Phf19的组蛋白结合能力，而该能力对于PRC2招募至染色质至关重要。本研究确立了miR-155–Phf19–PRC2作为调控CD8阳性T细胞分化的关键轴。靶向该微小RNA-多梳蛋白调控通路，有望通过表观遗传重编程CD8阳性T细胞命运，增强肿瘤免疫治疗效果。本研究对转导后第5天的过表达miR-155的Pmel-1型CD8阳性T细胞与对照组细胞的H3K27me3结合谱进行了比较分析。