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 - 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 -