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Article: Enhancing KDM5A and TLR activity improves the response to immune checkpoint blockade

TitleEnhancing KDM5A and TLR activity improves the response to immune checkpoint blockade
Authors
Issue Date2020
Citation
Science Translational Medicine, 2020, v. 12, n. 560, article no. eaax2282 How to Cite?
AbstractImmune checkpoint blockade (ICB) therapies are now established as first-line treatments for multiple cancers, but many patients do not derive long-term benefit from ICB. Here, we report that increased amounts of histone 3 lysine 4 demethylase KDM5A in tumors markedly improved response to the treatment with the programmed cell death protein 1 (PD-1) antibody in mouse cancer models. In a screen for molecules that increased KDM5A abundance, we identified one (D18) that increased the efficacy of various ICB agents in three murine cancer models when used as a combination therapy. D18 potentiated ICB efficacy through two orthogonal mechanisms: (i) increasing KDM5A abundance, which suppressed expression of the gene PTEN (encoding phosphatase and tensin homolog) and increased programmed cell death ligand 1 abundance through a pathway involving PI3K-AKT-S6K1, and (ii) activating Toll-like receptors 7 and 8 (TLR7/8) signaling pathways. Combination treatment increased T cell activation and expansion, CD103 tumor-infiltrating dendritic cells, and tumor-associated M1 macrophages, ultimately enhancing the overall recruitment of activated CD8+ T cells to tumors. In patients with melanoma, a high KDM5A gene signature correlated with KDM5A expression and could potentially serve as a marker of response to anti-PD-1 immunotherapy. Furthermore, our results indicated that bifunctional agents that enhance both KDM5A and TLR activity warrant investigation as combination therapies with ICB agents.
Persistent Identifierhttp://hdl.handle.net/10722/318863
ISSN
2023 Impact Factor: 15.8
2023 SCImago Journal Rankings: 6.510
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWang, Liangliang-
dc.contributor.authorGao, Yan-
dc.contributor.authorZhang, Gao-
dc.contributor.authorLi, Dan-
dc.contributor.authorWang, Zhenda-
dc.contributor.authorZhang, Jie-
dc.contributor.authorHermida, Leandro C.-
dc.contributor.authorHe, Lei-
dc.contributor.authorWang, Zhisong-
dc.contributor.authorSi, Jingwen-
dc.contributor.authorGeng, Shuang-
dc.contributor.authorAi, Rizi-
dc.contributor.authorNing, Fei-
dc.contributor.authorCheng, Chaoran-
dc.contributor.authorDeng, Haiteng-
dc.contributor.authorDimitrov, Dimiter S.-
dc.contributor.authorSun, Yan-
dc.contributor.authorHuang, Yanyi-
dc.contributor.authorWang, Dong-
dc.contributor.authorHu, Xiaoyu-
dc.contributor.authorWei, Zhi-
dc.contributor.authorWang, Wei-
dc.contributor.authorLiao, Xuebin-
dc.date.accessioned2022-10-11T12:24:44Z-
dc.date.available2022-10-11T12:24:44Z-
dc.date.issued2020-
dc.identifier.citationScience Translational Medicine, 2020, v. 12, n. 560, article no. eaax2282-
dc.identifier.issn1946-6234-
dc.identifier.urihttp://hdl.handle.net/10722/318863-
dc.description.abstractImmune checkpoint blockade (ICB) therapies are now established as first-line treatments for multiple cancers, but many patients do not derive long-term benefit from ICB. Here, we report that increased amounts of histone 3 lysine 4 demethylase KDM5A in tumors markedly improved response to the treatment with the programmed cell death protein 1 (PD-1) antibody in mouse cancer models. In a screen for molecules that increased KDM5A abundance, we identified one (D18) that increased the efficacy of various ICB agents in three murine cancer models when used as a combination therapy. D18 potentiated ICB efficacy through two orthogonal mechanisms: (i) increasing KDM5A abundance, which suppressed expression of the gene PTEN (encoding phosphatase and tensin homolog) and increased programmed cell death ligand 1 abundance through a pathway involving PI3K-AKT-S6K1, and (ii) activating Toll-like receptors 7 and 8 (TLR7/8) signaling pathways. Combination treatment increased T cell activation and expansion, CD103 tumor-infiltrating dendritic cells, and tumor-associated M1 macrophages, ultimately enhancing the overall recruitment of activated CD8+ T cells to tumors. In patients with melanoma, a high KDM5A gene signature correlated with KDM5A expression and could potentially serve as a marker of response to anti-PD-1 immunotherapy. Furthermore, our results indicated that bifunctional agents that enhance both KDM5A and TLR activity warrant investigation as combination therapies with ICB agents.-
dc.languageeng-
dc.relation.ispartofScience Translational Medicine-
dc.titleEnhancing KDM5A and TLR activity improves the response to immune checkpoint blockade-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1126/SCITRANSLMED.AAX2282-
dc.identifier.pmid32908002-
dc.identifier.scopuseid_2-s2.0-85090816918-
dc.identifier.volume12-
dc.identifier.issue560-
dc.identifier.spagearticle no. eaax2282-
dc.identifier.epagearticle no. eaax2282-
dc.identifier.eissn1946-6242-
dc.identifier.isiWOS:000567648900002-

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