RT Journal Article
SR Electronic
T1 Enhancing KDM5A and TLR activity improves the response to immune checkpoint blockade
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaax2282
DO 10.1126/scitranslmed.aax2282
VO 12
IS 560
A1 Wang, Liangliang
A1 Gao, Yan
A1 Zhang, Gao
A1 Li, Dan
A1 Wang, Zhenda
A1 Zhang, Jie
A1 Hermida, Leandro C.
A1 He, Lei
A1 Wang, Zhisong
A1 Si, Jingwen
A1 Geng, Shuang
A1 Ai, Rizi
A1 Ning, Fei
A1 Cheng, Chaoran
A1 Deng, Haiteng
A1 Dimitrov, Dimiter S.
A1 Sun, Yan
A1 Huang, Yanyi
A1 Wang, Dong
A1 Hu, Xiaoyu
A1 Wei, Zhi
A1 Wang, Wei
A1 Liao, Xuebin
YR 2020
UL http://stm.sciencemag.org/content/12/560/eaax2282.abstract
AB Immune checkpoint blockade immunotherapy for cancer has been achieving increasing prominence in recent years, but, unfortunately, it still only works for a subset of patients and tumor types. Wang et al. found that higher expression of lysine demethylase KDM5A in tumors correlates with their responses to immune checkpoint inhibition. The authors then found a way to take advantage of this mechanism using a compound that increased both KDM5A and a key immune checkpoint protein. At the same time, this compound also activated Toll-like receptor signaling, further stimulating antitumor immunity in multiple mouse models.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.