TY - JOUR
T1 - Enhancing KDM5A and TLR activity improves the response to immune checkpoint blockade
AU - Wang, Liangliang
AU - Gao, Yan
AU - Zhang, Gao
AU - Li, Dan
AU - Wang, Zhenda
AU - Zhang, Jie
AU - Hermida, Leandro C.
AU - He, Lei
AU - Wang, Zhisong
AU - Si, Jingwen
AU - Geng, Shuang
AU - Ai, Rizi
AU - Ning, Fei
AU - Cheng, Chaoran
AU - Deng, Haiteng
AU - Dimitrov, Dimiter S.
AU - Sun, Yan
AU - Huang, Yanyi
AU - Wang, Dong
AU - Hu, Xiaoyu
AU - Wei, Zhi
AU - Wang, Wei
AU - Liao, Xuebin
N1 - Funding Information:
This work was supported by a Chinese National Major Scientific Research Program grant from the Ministry of Science and Technology of the People's Republic of China (no. 2015CB943200 to X.L.), the National Natural Science Foundation of China (NSFC) (no. 21877067 to X.L. and no. 81673460 to D.W.), the China Postdoctoral Science Foundation (2017 M620753 to L.W.), Beijing Advanced Innovation Center for Human Brain Protection (to X.L.), and the Tsinghua-Peking Joint Center for Life Sciences Postdoctoral Foundation (to L.W.).
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved.
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
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U2 - 10.1126/SCITRANSLMED.AAX2282
DO - 10.1126/SCITRANSLMED.AAX2282
M3 - Article
C2 - 32908002
AN - SCOPUS:85090816918
SN - 1946-6234
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 560
M1 - eaax2282
ER -