<br>FOXO1 是 CAR T 细胞中记忆编程的主调节器,Nature

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FOXO1 是 CAR T 细胞中记忆编程的主调节器
Nature ( IF 50.5 ) Pub Date : 2024-04-10 , DOI: 10.1038/s41586-024-07300-8
Alexander E Doan ₁ , Katherine P Mueller _{2,

3,

4} , Andy Y Chen _{5,

6,

7} , Geoffrey T Rouin _{2,

3,

4} , Yingshi Chen _{2,

3,

4} , Bence Daniel _{5,

7,

8,

9,

10} , John Lattin ₁ , Martina Markovska _{2,

3,

4} , Brett Mozarsky _{2,

3,

4} , Jose Arias-Umana _{2,

3,

4} , Robert Hapke _{2,

3,

4} , In-Young Jung ₁₁ , Alice Wang ₂ , Peng Xu ₁ , Dorota Klysz ₁ , Gabrielle Zuern _{2,

3,

4} , Malek Bashti ₁ , Patrick J Quinn ₁ , Zhuang Miao ₉ , Katalin Sandor _{5,

7} , Wenxi Zhang _{5,

7} , Gregory M Chen _{4,

12} , Faith Ryu _{2,

3,

4} , Meghan Logun _{4,

13} , Junior Hall _{2,

14,

15} , Kai Tan _{2,

14,

15} , Stephan A Grupp _{2,

14,

15} , Susan E McClory _{2,

14} , Caleb A Lareau _{5,

7,

16} , Joseph A Fraietta _{4,

11,

12,

15} , Elena Sotillo ₁ , Ansuman T Satpathy _{5,

7,

16} , Crystal L Mackall _{1,

16,

17,

18} , Evan W Weber _{2,

3,

4,

14,

15,

16}

Affiliation

Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.
Department of Bioengineering, Stanford University, Stanford, CA, USA.
Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
Department of Genetics, Stanford University, Stanford, CA, USA.
Genentech, South San Francisco, CA, USA.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
Department of Pediatrics, Stanford University, Stanford, CA, USA.
Department of Medicine, Stanford University, Stanford, CA, USA.

嵌合抗原受体 (CAR) T 细胞疗法的一个主要限制是这些细胞在体内的持久性较差¹ 。 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在和临床疗效相关^2,3,4,5,6 ，这表明记忆程序可能支持持久的 CAR T 细胞功能。在这里，我们证明转录因子 FOXO1 负责促进人类 CAR T 细胞的记忆和抑制疲劳。内源性FOXO1的药理学抑制或基因编辑会减少记忆相关基因的表达，促进疲劳样表型并损害 CAR T 细胞的抗肿瘤活性。 FOXO1 的过度表达诱导了与 T 细胞记忆一致的基因表达程序，并增加了 FOXO1 结合基序的染色质可及性。过表达 FOXO1 的 CAR T 细胞在慢性刺激的情况下保留了其功能、记忆潜力和代谢适应性，并在体内表现出增强的持久性和肿瘤控制。相比之下，TCF1（由TCF7编码）的过度表达不会强制执行规范记忆程序或增强 CAR T 细胞的效力。值得注意的是，FOXO1 活性与接受 CAR T 细胞或肿瘤浸润淋巴细胞治疗的患者的积极临床结果相关，强调了 FOXO1 在癌症免疫治疗中的临床相关性。我们的结果表明，过度表达 FOXO1 可以增加人类 CAR T 细胞的抗肿瘤活性，并强调记忆重编程是优化治疗性 T 细胞状态的一种广泛适用的方法。

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

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 efficacy^2,3,4,5,6, 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.

更新日期：2024-04-11

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