Authors: Hsing-Chen Tsai, Yi-Chieh Wu, Yu-Ting Lee, Meng-Wei Chou, Shu-Yung Lin, Sheng-Yao Su, Chia-Lang Hsu, Nai-Wen Chang, Yi-Jhen Huang, Yi-Hsiu Juan, Hsuan-Hsuan Lu, Pei-Shan Wu, Miao-Hsia Lin, Li-Chung Hsu, Yen-Ling Chiu, Shih-Yu Chen, Chong-Jen Yu
Published: 2025-04-21
DOI: 10.1158/1538-7445.am2025-4838
Source: Full article
T cell exhaustion, a dysfunctional state caused by prolonged antigen exposure, presents a major challenge in cancer immunotherapy. While immune checkpoint inhibitors show therapeutic promise, they fail to rejuvenate T cells in a terminally exhaustion state, potentially due to epigenetic barriers. We hypothesized that targeting epigenetic regulators may provide novel therapeutic strategies to overcome these barriers, thereby rescuing terminally exhausted T cells. In this project, we used malignant pleural effusions from advanced lung cancer patients as a source of primary exhausted T cells. Through high-throughput screening of an epigenetic compound library, we identified several bromodomain inhibitors (BETis) as potent enhancers of T cell polyfunctionality in primary human T cells. Treatment with BETis, like JQ1, reduces inhibitory receptor expression and increases effector cytokine production. Transcriptomic and ATAC-seq profiling revealed that JQ1 modulates key metabolic pathways and induces chromatin accessibility changes in primary effusion-infiltrative T cells. Untargeted metabolomics showed that JQ1 expands the polyamine spermidine pool in T cells. Inhibition of ornithine decarboxylase (ODC1), a key enzyme in polyamine biosynthesis, diminishes JQ1’s reinvigorating effects on these T cells. scRNA-seq analysis revealed that JQ1 reduces terminally exhausted T cells and promotes the expansion of progenitor exhausted T cells, which are more responsive to checkpoint inhibitors, by upregulating ODC1 and its upstream regulator, MYC. Notably, adoptive transfer of JQ1-treated T cells significantly reduced tumor-associated MPE in a syngeneic mouse model. Our study demonstrates that BET inhibitors enhance T cell polyfunctionality and modulate terminally exhausted T cells through metabolic reprogramming, notably by upregulating the polyamine biosynthesis pathway. These findings highlight the potential of epigenetic-based cancer immunotherapy for novel therapeutic strategies.