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

Liangliang Wang, Yan Gao, Gao Zhang, Dan Li, Zhenda Wang, Jie Zhang, Leandro C. Hermida, Lei He, Zhisong Wang, Jingwen Si, Shuang Geng, Rizi Ai, Fei Ning, Chaoran Cheng, Haiteng Deng, Dimiter S. Dimitrov, Yan Sun, Yanyi Huang, Dong Wang, Xiaoyu HuZhi Wei, Wei Wang, Xuebin Liao

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Immune 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.

Original languageEnglish (US)
Article numbereaax2282
JournalScience Translational Medicine
Issue number560
StatePublished - Sep 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Medicine


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