Abstract
Loss of LSD1 enhances tumor immunogenicity and sensitizes refractory mouse melanoma to anti–PD-1 therapy.
Major finding: Loss of LSD1 enhances tumor immunogenicity and sensitizes refractory mouse melanoma to anti–PD-1 therapy.
Mechanism: LSD1 blocks repetitive element expression and drives AGO2 stabilization to decrease dsRNA and TIL levels.
Impact: Therapeutic targeting of LSD1 may enhance the antitumor efficacy of immune checkpoint blockade.
DNA methyltransferase inhibitors have been shown to activate the cytosolic antiviral double-stranded RNA (dsRNA) sensing pathway to promote type I IFN activation, associated with increased tumor response to anti-CTLA4 therapy, but how chromatin regulators modulate tumor immunity and immunotherapy has not been fully ascertained. Sheng, LaFleur, and colleagues screened compounds to identify chromatin regulators that promote the upregulation of endogenous retroviral elements (ERV) and activate type I IFNs and identified the histone demethylase LSD1, which was found to be often overexpressed in patient tumors. LSD1 repressed the expression of ERVs, and LSD1 ablation promoted intracellular dsRNA accumulation and the upregulation of type I IFN–related genes. Knockdown of individual dsRNA sensors in LSD1-ablated cells identified TLR3 and MDA5 as critical for LSD1 loss–mediated IFN signaling. Further, LSD1 knockdown resulted in the decreased expression of DICER, AGO2, and TRBP2, all of which are components of the RNA-induced silencing complex, which mediates gene silencing by processing dsRNA. AGO2 knockdown resulted in dsRNA accumulation, and knockdown of AGO2, DICER, or TRBP2 resulted in activated IFN signalling; additionally, LSD1-mediated demethylation of AGO2 promoted AGO2 stabilization. LSD1 ablation resulted in decreased proliferation in vitro, which was partially rescued by inhibition of IFN pathway genes. LSD1 ablation in mouse melanoma cells resulted in decreased tumor growth and dsRNA stress–dependent antitumor T-cell immunity only in immunocompetent, but not immunodeficient, mice. LSD1-depleted tumors exhibited increased numbers of CD8+ tumor-infiltrating lymphocytes, elevated expression of MHC class I antigens, and the immune checkpoint PD-L1; similarly, LSD1 expression levels were inversely correlated with T-cell infiltration in patient tumors. Treatment with anti–PD-1 antibody resulted in greater tumor suppression and increased survival in mice with LSD1-depleted tumors compared to mice with LSD1-replete tumors. Thus, LSD1 is a negative regulator of antitumor immunity and responsiveness to immunotherapy, and inhibition of LSD1 potentially turns “cold” tumors “hot.”
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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