美国宾夕法尼亚大学Evan W. Weber和斯坦福大学医学院Crystal L. Mackall研究组合作取得一项新突破。他们发现FOXO1是嵌合抗原受体（CAR）T细胞记忆编程的主调节因子。相关论文发表在2024年4月10日出版的《自然》杂志上。

研究人员发现转录因子FOXO1促进人CAR T细胞的记忆和抑制细胞耗竭。药物抑制或基因编辑内源性FOXO1会减少记忆相关基因的表达，促进衰竭样表型的形成，并损害CAR T细胞的抗肿瘤活性。过表达FOXO1会诱导与T细胞记忆一致的基因表达程序，并增加FOXO1结合基序的染色质可及性。过表达FOXO1的CAR T细胞在慢性刺激条件下仍能保持其功能、记忆潜能和新陈代谢能力，并在体内表现出更强的持久性和肿瘤控制能力。

相比之下，TCF1（由TCF7编码）的过表达并没有增加典型记忆程序或增强CAR T细胞的效力。值得注意的是，FOXO1的活性与CAR T细胞或肿瘤浸润淋巴细胞治疗患者的临床疗效相关，这突显了FOXO1在癌症免疫治疗中的临床意义。该研究结果表明，过表达FOXO1可以提高人CAR T细胞的抗肿瘤活性，并暗示记忆重编程是优化治疗性T细胞状态的一种广泛适用方法。

据悉，CAR T细胞疗法的一个主要局限是这些细胞不能持续在体内存活。CAR T细胞中记忆相关基因的表达与其在患者体内的长期存活和临床疗效有关，这表明记忆程序可能是CAR T细胞持久功能的基础。

附：英文原文

Title: FOXO1 is a master regulator of memory programming in CAR T cells

Author: Doan, Alexander E., Mueller, Katherine P., Chen, Andy Y., Rouin, Geoffrey T., Chen, Yingshi, Daniel, Bence, Lattin, John, Markovska, Martina, Mozarsky, Brett, Arias-Umana, Jose, Hapke, Robert, Jung, In-Young, Wang, Alice, Xu, Peng, Klysz, Dorota, Zuern, Gabrielle, Bashti, Malek, Quinn, Patrick J., Miao, Zhuang, Sandor, Katalin, Zhang, Wenxi, Chen, Gregory M., Ryu, Faith, Logun, Meghan, Hall, Junior, Tan, Kai, Grupp, Stephan A., McClory, Susan E., Lareau, Caleb A., Fraietta, Joseph A., Sotillo, Elena, Satpathy, Ansuman T., Mackall, Crystal L., Weber, Evan W.

Issue&Volume: 2024-04-10

Abstract: A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2,3,4,5,6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.

DOI: 10.1038/s41586-024-07300-8

Source: https://www.nature.com/articles/s41586-024-07300-8