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Published on: March 7, 2011
LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade
Wanqiang Sheng1, Martin W LaFleur2, Thao H Nguyen3
1Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Chromatin regulators play a broad role in regulating gene expression and, when gone awry, can lead to cancer. Here, we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to double-stranded RNA (dsRNA) stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8+ T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy.
Insights
Inhibition of LSD1 in cancer cells boosts anti-tumor immunity by increasing repetitive element expression and activating interferon. This approach enhances immunotherapy response, suggesting a new cancer treatment strategy.
Area of Science:
- Cancer Biology
- Immunology
- Epigenetics
Background:
- Chromatin regulators are crucial for gene expression; their dysregulation contributes to cancer.
- The histone demethylase LSD1 (Lysine Specific Demethylase 1) is implicated in various cancers.
Purpose of the Study:
- To investigate the role of LSD1 in regulating gene expression and anti-tumor immunity.
- To explore LSD1 inhibition as a potential cancer therapeutic strategy.
Main Methods:
- Ablation of LSD1 in cancer cells.
- Analysis of repetitive element and RNA-induced silencing complex (RISC) component expression.
- Assessment of double-stranded RNA (dsRNA) stress and type 1 interferon activation.
- Evaluation of tumor immunogenicity, T cell infiltration, and response to anti-PD-1 therapy in mouse models.
- Analysis of TCGA data for correlation between LSD1 expression and CD8+ T cell infiltration.
Main Results:
- LSD1 ablation increased repetitive element and endogenous retroviral element (ERV) expression.
- Decreased expression of RISC components led to dsRNA stress and type 1 interferon activation.
- LSD1 depletion enhanced tumor immunogenicity and T cell infiltration, improving responses to anti-PD-1 therapy in refractory melanoma.
- TCGA data revealed an inverse correlation between LSD1 expression and CD8+ T cell infiltration in human cancers.
Conclusions:
- LSD1 inhibition potentiates anti-tumor immunity and enhances responsiveness to immunotherapy.
- LSD1 is a key inhibitor of anti-tumor immunity.
- Combining LSD1 inhibition with PD-(L)1 blockade presents a promising novel cancer treatment strategy.
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