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Epigenetic regulators are a class of promising targets in 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 TGFβ 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 TGFβ 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 rechallenge. Thus, combining LSD1 inhibition with blockade of TGFβ and PD-1 may represent a promising triple combination therapy for treating certain refractory tumors. SIGNIFICANCE: Cotargeting LSD1 and TGFβ cooperatively elevates intratumoral CD8+ T-cell infiltration and unleashes their cytotoxicity, leading to tumor eradication upon anti-PD-1 treatment. Our findings illustrate a duality of epigenetic perturbations in immunotherapy and implicate the combination of LSD1 inhibition with dual PD-1/TGFβ blockade in treating certain poorly immunogenic tumors.This article is highlighted in the In This Issue feature, p. 1861.

Original publication

DOI

10.1158/2159-8290.cd-20-0017

Type

Journal article

Journal

Cancer discovery

Publication Date

08/2021

Volume

11

Pages

1970 - 1981

Addresses

Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. wanqiang_sheng@zju.edu.cn yang.shi@ludwig.ox.ac.uk.

Keywords

Cell Line, Tumor, Animals, Mice, Inbred C57BL, Humans, Mice, Transforming Growth Factor beta, Immunotherapy, Female, Histone Demethylases, Programmed Cell Death 1 Receptor, Immune Checkpoint Inhibitors