LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade
Open accessAbstract
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.
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DNA demethylating agents can induce a type I IFN response in cancer cells through de-repression of endogenous retroviruses and activation of the MDA5-MAVS pathway.
“multiple studies have shown that DNA demethylating agents among other epigenetic modulators can induce a type I IFN response in cancer cells through the de-repression of endogenous retroviruses (ERVs) and activation of the MDA5-MAVS pathway38–40.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [40]
The Discussion (Intracellular dsRNA homeostasis; page not available) reports that DNMT inhibitors increase ERV transcription and IFN activation. The Results (TLR3 and MDA5 sense dsRNA accumulation; page not available) show MDA5–MAVS involvement after LSD1 inhibition, not after treatment with DNA demethylating agents. Thus the source does not establish that full pathway for those agents. (LLM, conf=0.88)
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- Authors
- Sheng, W., LaFleur, M. W., Nguyen, T. H., Chen, S., Chakravarthy, A., Conway, J. R., Li, Y., Chen, H., Yang, H., Hsu, P.-H., Van Allen, E. M., Freeman, G. J., De Carvalho, D. D., He, H. H., Sharpe, A. H., & Shi, Y.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- University Health Network (CA)
- National University of Singapore (SG)
- National Taiwan Ocean University (TW)
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Sharpe, Arlene H.
- Shi, Yang
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 174
- Issue
- 3
- Pages
- 549-563.e19
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6063761
- OpenAlex
- W2809237949
- Cited by
- 693
- References
- 6
- Citations by year
- 2026: 60 · 2025: 81 · 2024: 95 · 2023: 118 · 2022: 90 · 2021: 104 · 2020: 73 · 2019: 57 · 2018: 15
- FWCI
- 23.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 CA118487, R01 GM117264, R35 CA210104, T32CA207021)
- Boston Children's Hospital
- Evergrande Center for Immunologic Diseases
- Ludwig Center at Harvard Medical School
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- LSD1, histone demethylase, antitumor immunity, immune checkpoint blockade, anti-PD-1 therapy, endogenous retroviruses, repetitive elements, RNA-induced silencing complex, type I interferon, CD8+ T cell infiltration, melanoma, chromatin regulators, immunogenicity
- MeSH terms
- Animals, Chromatin, Combined Modality Therapy, Gene Expression Regulation, Humans, Immunity, Cellular, Immunotherapy, Interferon Type I, RNA, Double-Stranded, T-Lymphocytes, Endogenous Retroviruses, RNA-Induced Silencing Complex, Cell Line, Tumor, Mice, Histone Demethylases, Programmed Cell Death 1 Receptor, MCF-7 Cells
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