Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, 19140, USA.
Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA.
Nat Commun. 2017 Dec 14;8(1):2125. doi: 10.1038/s41467-017-02187-8.
Memory T cells sustain effector T-cell production while self-renewing in reaction to persistent antigen; yet, excessive expansion reduces memory potential and impairs antitumor immunity. Epigenetic mechanisms are thought to be important for balancing effector and memory differentiation; however, the epigenetic regulator(s) underpinning this process remains unknown. Herein, we show that the histone methyltransferase Ezh2 controls CD8 T memory precursor formation and antitumor activity. Ezh2 activates Id3 while silencing Id2, Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh2 and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors. Engineering T cells with an Akt-insensitive Ezh2 mutant markedly improves their memory potential and capability of controlling tumor growth compared to transiently inhibiting Akt. These findings establish Akt-mediated phosphorylation of Ezh2 as a critical target to potentiate antitumor immunotherapeutic strategies.
记忆 T 细胞在持续抗原刺激下通过自我更新来维持效应 T 细胞的产生；然而，过度扩增会降低记忆潜能并损害抗肿瘤免疫。表观遗传机制被认为对平衡效应器和记忆分化很重要；然而，支持这一过程的表观遗传调节剂尚不清楚。本文中，我们发现组蛋白甲基转移酶 Ezh2 控制 CD8 T 记忆前体细胞的形成和抗肿瘤活性。Ezh2 激活 Id3 同时沉默 Id2、Prdm1 和 Eomes，促进记忆前体细胞的扩增及其分化为功能性记忆细胞。Akt 激活使 Ezh2 磷酸化，从而降低其对这些转录程序的控制，导致效应器分化增强，而 T 记忆前体细胞减少。与短暂抑制 Akt 相比，用对 Akt 不敏感的 Ezh2 突变体工程化 T 细胞可显著提高其记忆潜能和控制肿瘤生长的能力。这些发现确定 Akt 介导的 Ezh2 磷酸化是增强抗肿瘤免疫治疗策略的关键靶点。
