Wang, Gao, Zhang, and Li et al. defined a gene profile associated with histone 3 lysine 4 demethylase (KDM5A) expression that correlates with anti-PD-1 responses in patients with melanoma. Anti-PD-1 responses were greater in mice bearing tumors with elevated KDM5A. KDM5A reduced PTEN transcription, which increased PI3K-AKT-S6K1 signaling and hence PD-L1 levels. D18, a TLR7/8 agonist, increased KDM5A and PD-L1 levels in tumor cells and synergized with anti-PD-1 in mouse cancer models. D18 with anti-PD-1 alone, and also with anti-Tim3 increased intratumoral CD103+ DCs, M1 macrophages, TH1 CD4+ T, CD8+ killer T, and Tcm cells.
Contributed by Paula Hochman
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.
Author Info: (1) School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Beijing Advanced Innovation Center for Human
Author Info: (1) 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. (2) 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. (3) Department of Neurosurgery and The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA. (4) 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. (5) 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. (6) Department of Computer Science, College of Computing Sciences, New Jersey Institute of Technology, Neswark, NJ 07102, USA. (7) Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, College Park, MD 20742, USA. (8) 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. (9) 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. (10) 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. (11) Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), College of Chemistry, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. (12) Department of Chemistry and Biochemistry, 9500 Gilman Drive, UC San Diego, La Jolla, CA 92093, USA. (13) Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. (14) Department of Computer Science, College of Computing Sciences, New Jersey Institute of Technology, Neswark, NJ 07102, USA. (15) MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China. (16) Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. (17) Lanzhou Institute of Husbandry and Pharmaceutical Science of CAAS, Lanzhou 730050, China. (18) Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), College of Chemistry, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. (19) School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. (20) Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. xiaoyuhu@mail.tsinghua.edu.cn zhiwei04@gmail.com wei-wang@ucsd.edu liaoxuebin@mail.tsinghua.edu.cn. (21) Department of Computer Science, College of Computing Sciences, New Jersey Institute of Technology, Neswark, NJ 07102, USA. xiaoyuhu@mail.tsinghua.edu.cn zhiwei04@gmail.com wei-wang@ucsd.edu liaoxuebin@mail.tsinghua.edu.cn. (22) Department of Chemistry and Biochemistry, 9500 Gilman Drive, UC San Diego, La Jolla, CA 92093, USA. xiaoyuhu@mail.tsinghua.edu.cn zhiwei04@gmail.com wei-wang@ucsd.edu liaoxuebin@mail.tsinghua.edu.cn. (23) 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. xiaoyuhu@mail.tsinghua.edu.cn zhiwei04@gmail.com wei-wang@ucsd.edu liaoxuebin@mail.tsinghua.edu.cn.
