Abstract 4838: Epigenetic modulation of polyamine biosynthetic pathways rectifies T cell dysfunction to enhance anti-tumor immunity in lung cancer
Journal
Cancer Research
Journal Volume
85
Journal Issue
8_Supplement_1
Start Page
4838-4838
ISSN
0008-5472
1538-7445
Date Issued
2025-04-21
Author(s)
Wu, Yi-Chieh
Lee, Yu-Ting
Chou, Meng-Wei
Lin, Shu-Yung
Su, Sheng-Yao
Hsu, Chia-Lang
Chang, Nai-Wen
Huang, Yi-Jhen
Juan, Yi-Hsiu
Lu, Hsuan-Hsuan
Wu, Pei-Shan
Lin, Miao-Hsia
Hsu, Li-Chung
Chiu, Yen-Ling
Chen, Shih-Yu
Yu, Chong-Jen
Abstract
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.
Publisher
American Association for Cancer Research (AACR)
Type
journal article