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Updated: Jun 25, 2025
Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
Priming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells
Fengqi Qiu1, Peishan Jiang1,2, Guiheng Zhang1,2
1Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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.
Insights
Targeting histone demethylase LSD1 with inhibitors improves T cell persistence and antitumor effects. This approach enhances CD8+ T cell memory, polyfunctionality, and efficacy in various cancer models, offering a new strategy for adoptive T cell therapy.
Area of Science:
- Immunology
- Epigenetics
- Cancer Therapy
Background:
- Adoptively transferred T cells show limited antitumor efficacy due to poor persistence and exhaustion.
- Mechanisms underlying T cell exhaustion and strategies to overcome it require further investigation.
Purpose of the Study:
- To investigate the role of histone demethylase LSD1 in T cell exhaustion and antitumor efficacy.
- To evaluate the potential of LSD1 inhibition as a strategy to enhance adoptive T cell therapy.
Main Methods:
- In vitro activation and expansion of CD8+ T cells with LSD1 inhibitors.
- Assessment of T cell phenotype, cytokine production, exhaustion markers, and persistence.
- Evaluation of antitumor efficacy in mouse models of solid tumors and humanized models.
Main Results:
- Transient LSD1 inhibition improved memory phenotype, cytokine production, and persistence of mouse CD8+ T cells.
- LSD1 inhibition enhanced antitumor effects of OT1 cells in solid tumor models, alone and with PD-1 blockade.
- Priming with LSD1 inhibitors increased polyfunctionality and persistence of human CD8+ T cells and CD19-CAR T cells.
Conclusions:
- Pharmacological inhibition of LSD1 reshapes the epigenome of T cells, enhancing their antitumor functions.
- LSD1 inhibition represents a promising strategy to improve the efficacy and persistence of adoptive T cell therapy for various cancers.
