肿瘤细胞治疗研究
英文原题：BCL11B targeting in tumor CD8 (+) T cells amplifies anti-tumor response by blocking exhaustion while promoting stemness and cytotoxicity.
BCL11B targeting in tumor CD8 (+) T cells amplifies anti-tumor response by blocking exhaustion while promoting stemness and cytotoxicity.
未标记：肿瘤浸润性CD8+ T细胞（TILs）进展为终末耗竭状态（Ttex），其功能受损且不可再生。
未标注：肿瘤浸润性 CD8+ T 细胞（TILs）进展为终末耗竭状态（Ttex），其功能受损且不可更新。然而其前体细胞（Tpex）可更新，并能产生有效的效应细胞。我们从以下观察出发：接受检查点抑制剂治疗的黑色素瘤患者，当其 T 细胞具有低 BCL11B mRNA 时，生存期增加。与此一致，在 CD8+ TILs 中敲除 Bcl11b 在小鼠黑色素瘤和卵巢癌模型中赋予了更优的抗肿瘤反应。Bcl11b KO TILs 未能进展为 Ttex 状态，并保留了升高的干性。Bcl11b 通过抑制控制干性的必需转录因子（TF）的表达，以及反过来通过复杂的表观遗传控制促进耗竭相关 TF 和抑制性受体基因的表达，来发挥其作用。此外，Bcl11b KO CD8+ T 细胞显示出增加的 Ag 特异性细胞溶解活性以及升高的 Gzmb 和 Prf1 蛋白，但其 mRNA 并未增加，然而表现出与翻译相关基因的更高表达。此外，CRISPR-CAS9 介导的 BCL11B 缺失在一名对自体 TILs 过继细胞治疗反应不佳的患者的人类 TILs 中，改善了其细胞溶解活性，并促进了干性相关 TF TCF1 的表达，表明其潜在的治疗用途。亮点：过继转移 Bcl11b KO CD8+ TILs 在减少肿瘤负荷方面优于 WT Bcl11b 消融重编程 TILs，并损害向 Ttex 状态的进展 Bcl11b KO CD8+ T 细胞具有升高的细胞毒性，且仅杀伤 Ag-MHCI 靶标 在无应答者 ACT-TIL 中缺失 BCL11B 可改善细胞溶解活性并升高 TCF1。
UNLABELLED: Tumor infiltrating CD8 + T cells (TILs) progress to a state of terminal exhaustion (Ttex) which have impaired functionality and are nonrenewable. However their precursors (Tpex) are renewable and can generate efficient effector cells. We started from the observation that melanoma patients undergoing therapy with checkpoint inhibitors show increased survival when their T cells have low BCL11B mRNA. In line with this, ablation of Bcl11b in CD8 + TILs conferred a superior anti-tumor response in murine melanoma and ovarian cancer models. Bcl11b KO TILs failed to progress to the Ttex state and retained elevated stemness. Bcl11b exerted its role by repressing expression of essential transcription factors (TF) controlling stemness, and conversely by promoting expression of exhaustion-associated TFs and inhibitory receptor genes, through complex epigenetic control. In addition, Bcl11b KO CD8 + T cells showed increased Ag-specific cytolytic activity and elevated Gzmb and Prf1 proteins, but no increase in their mRNAs, however presented higher expression of genes with role in translation. Furthermore, CRISPR-CAS9-mediated deletion of BCL11B in human TILs from a patient with poor response to adoptive cell therapy with autologous TILs, improved their cytolytic activity and promoted expression of the stemness-associated TF TCF1, underlying its potential therapeutic use. HIGHLIGHTS: Adoptive transfer of Bcl11b KO CD8 + TILs surpasses WT in tumor burden reduction Bcl11b ablation reprograms TILs and impairs the progression to Ttex state Bcl11b KO CD8 + T cells have elevated cytotoxicity and kill only Ag-MHCI targets BCL11B deletion in nonresponder ACT-TIL improves cytolytic activity and elevates TCF1.
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