Research ArticleCancer

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

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Science Translational Medicine  09 Sep 2020:
Vol. 12, Issue 560, eaax2282
DOI: 10.1126/scitranslmed.aax2282

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All roads lead to antitumor immunity

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.

Abstract

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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