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Cell. 2018 Jul 26;174(3):549-563.e19. doi: 10.1016/j.cell.2018.05.052. Epub 2018 Jun 21.

LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade.

Author information

1
Division 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.
2
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2M9, Canada.
5
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
6
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
7
Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung City 202, Taiwan.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
9
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: arlene_sharpe@hms.harvard.edu.
10
Division 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. Electronic address: yang_shi@hms.harvard.edu.

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.

KEYWORDS:

LSD1; MHC-1; PD-1/PD-L1; RISC; T cell infiltration; anti-tumor immunity; dsRNA; endogenous retroviral element; immune checkpoint blockade; interferon

PMID:
29937226
PMCID:
PMC6063761
[Available on 2019-07-26]
DOI:
10.1016/j.cell.2018.05.052

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