癌症研究
免疫疗法
免疫原性细胞死亡
CD8型
细胞毒性T细胞
细胞毒性
封锁
免疫系统
癌症免疫疗法
T细胞
肿瘤微环境
免疫学
免疫检查点
生物
受体
体外
生物化学
作者
Wanqiang Sheng,Yi Liu,Damayanti Chakraborty,Brian Debo,Yang Shi
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2021-03-09
卷期号:11 (8): 1970-1981
被引量:45
标识
DOI:10.1158/2159-8290.cd-20-0017
摘要
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.
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