Priming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells

Fengqi Qiu, Peishan Jiang, Guiheng Zhang, Jie An, Kexin Ruan, Xiaowen Lyu (), Jianya Zhou () and Wanqiang Sheng ()
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Fengqi Qiu: Zhejiang University School of Medicine
Peishan Jiang: Zhejiang University School of Medicine
Guiheng Zhang: Zhejiang University School of Medicine
Jie An: Zhejiang University School of Medicine
Kexin Ruan: Zhejiang University School of Medicine
Xiaowen Lyu: Xiamen University
Jianya Zhou: Zhejiang University School of Medicine
Wanqiang Sheng: Zhejiang University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The antitumor efficacy of adoptively transferred T cells is limited by their poor persistence, in part due to exhaustion, but the underlying mechanisms and potential interventions remain underexplored. Here, we show that targeting histone demethylase LSD1 by chemical inhibitors reshapes the epigenome of in vitro activated and expanded CD8+ T cells, and potentiates their antitumor efficacy. Upon T cell receptor activation and IL-2 signaling, a timely and transient inhibition of LSD1 suffices to improve the memory phenotype of mouse CD8+ T cells, associated with a better ability to produce multiple cytokines, resist exhaustion, and persist in both antigen-dependent and -independent manners after adoptive transfer. Consequently, OT1 cells primed with LSD1 inhibitors demonstrate an enhanced antitumor effect in OVA-expressing solid tumor models implanted in female mice, both as a standalone treatment and in combination with PD-1 blockade. Moreover, priming with LSD1 inhibitors promotes polyfunctionality of human CD8+ T cells, and increases the persistence and antitumor efficacy of human CD19-CAR T cells in both leukemia and solid tumor models. Thus, pharmacological inhibition of LSD1 could be exploited to improve adoptive T cell therapy.

Date: 2024
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DOI: 10.1038/s41467-024-48607-4

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