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Mol. Ther., Apr 05 2024, S1525-0016(24)00220-X | https://doi.org/10.1016/j.ymthe.2024.04.004 Decoding and Overcoming T cell Exhaustion: Epigenetic and Transcriptional Dynamics in CAR-T Cells Against Solid Tumors

Taeyoung Ahn^1,#, Eun-Ah Bae^2,#, Hyungseok Seo ¹

¹Laboratory of Cell & Gene Therapy, Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826 Republic of Korea

²Laboratory of Immunology, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea

^#These authors contributed equally to this work.

Correspondence to Hyungseok Seo

Abstract

T cell exhaustion, which is observed in various chronic infections and malignancies, is characterized by elevated expression of multiple inhibitory receptors, impaired effector functions, decreased proliferation, and reduced cytokine production. Notably, while adoptive T cell therapies, such as chimeric antigen receptor (CAR)-T therapy, have shown promise in treating cancer and other diseases, the efficacy of these therapies is often compromised by T cell exhaustion. It is imperative, therefore, to understand the mechanisms underlying this exhaustion to promote advances in T cell-related therapies. Here, we divided exhausted T cells into three distinct subsets according to their developmental and functional profiles: stem-like progenitor cells (Tex ^Prog), intermediately exhausted cells (Tex ^int), and terminally exhausted cells (Tex ^term). These subsets are carefully regulated by synergistic mechanisms that involve transcriptional and epigenetic modulators. Key transcription factors, such as TCF1, BACH2, and TOX, are crucial for defining and sustaining exhaustion phenotypes. Concurrently, epigenetic regulators, such as TET2 and DNMT3A, shape the chromatin dynamics that direct T cell fate. The interplay of these molecular drivers has recently been highlighted in CAR-T research, revealing promising therapeutic directions. Thus, a profound understanding of exhausted T cell hierarchies and their molecular complexities may reveal innovative and improved tumor treatment strategies.

논문정보

형식Review Paper
게재일2024년 04월 (BRIC 등록일 2024-04-08)
연구진국내 연구진
분야 의약학 > 면역의학

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