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Simultaneous Inhibition of LSD1 and TGF-β Enables Eradication of Poorly Immunogenic Tumors with anti-PD-1 Treatment

ABSTRACT: Epigenetic regulators are a class of promising targets in the combination with immune checkpoint inhibitors for cancer treatment, but the impact of the broad effects of perturbing epigenetic regulators on tumor immunotherapy remains to be fully explored. Here we show that ablation of the histone demethylase LSD1 in multiple tumor cells induces TGF-β expression, which exerts an inhibitory effect on T cell immunity through suppressing the cytotoxicity of intratumoral CD8+ T cells and consequently dampens the antitumor effect of LSD1 ablation-induced T cell infiltration. Importantly, concurrent depletion of LSD1 and TGF-β in combination with PD-1 blockade significantly increases both CD8+ T cell infiltration and cytotoxicity, leading to eradication of poorly immunogenic tumors and a long-term protection from tumor re-challenge. Thus, combining LSD1 inhibition with blockade of TGF-β and PD-1 may represent a promising triple combination therapy for treating certain refractory tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE161569 | GEO | 2021/03/09

REPOSITORIES: GEO

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