School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human Brain Protection, Tsinghua University, Beijing 100084, China.
Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100006, China.
Sci Transl Med. 2020 Sep 9;12(560). doi: 10.1126/scitranslmed.aax2282.
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 (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 gene signature correlated with 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.
免疫检查点阻断 (ICB) 疗法现已成为多种癌症的一线治疗方法，但许多患者并未从中长期获益。在这里，我们报告称，肿瘤中组蛋白 3 赖氨酸 4 去甲基化酶 KDM5A 的含量增加，可显著改善 PD-1 抗体治疗在小鼠癌症模型中的疗效。在筛选增加 KDM5A 丰度的分子时，我们鉴定出一种（D18），当作为联合治疗使用时，它可增强三种小鼠癌症模型中各种 ICB 药物的疗效。D18 通过两种正交机制增强 ICB 的疗效：（i）增加 KDM5A 的丰度，这通过涉及 PI3K-AKT-S6K1 的途径抑制基因（编码磷酸酶和张力蛋白同源物）的表达，并增加程序性细胞死亡配体 1 的丰度，以及（ii）激活 Toll 样受体 7 和 8（TLR7/8）信号通路。联合治疗增加了 T 细胞的激活和扩增、CD103 肿瘤浸润树突状细胞和肿瘤相关 M1 巨噬细胞，最终增强了激活的 CD8 T 细胞向肿瘤的整体募集。在黑色素瘤患者中，高基因特征与表达相关，可能可作为对抗 PD-1 免疫治疗反应的标志物。此外，我们的结果表明，增强 KDM5A 和 TLR 活性的双功能药物值得作为与 ICB 药物联合治疗的研究。
