Targeting KDM4 family epigenetically triggers antitumour immunity via enhancing tumour-intrinsic innate sensing and immunogenicity

Abstract

Despite the remarkable clinical efficacy of cancer immunotherapy, considerable patients fail to benefit from it due to primary or acquired resistance. Tumours frequently hijack diverse epigenetic mechanisms to evade immune detection, thereby highlighting the potential for pharmacologically targeting epigenetic regulators to restore the impaired immunosurveillance and re-sensitise tumours to immunotherapy. Herein, we demonstrated that KDM4-targeting chemotherapeutic drug JIB-04, epigenetically triggered the tumour-intrinsic innate immune responses and immunogenic cell death (ICD), resulting in impressive antitumour effects. Specifically, JIB-04 induced H3K9 hypermethylation through specific inhibition of the KDM4 family (KDM4A-D), leading to impaired DNA repair signalling and subsequent DNA damage. As a result, JIB-04 not only activated the tumour-intrinsic cyclic GMP-AMP synthase (cGAS)-STING pathway via DNA-damage-induced cytosolic DNA accumulation, but also promoted ICD, releasing numerous damage-associated molecular patterns. Furthermore, JIB-04 induced adaptive resistance through the upregulation of programmed death-ligand 1 (PD-L1), which could be overcome with additional PD-L1 blockade. In human tumours, KDM4B expression was negatively correlated with clinical outcomes, type I interferon signatures, and responses to immunotherapy. In conclusion, our results demonstrate that targeting KDM4 family can activate tumour-intrinsic innate sensing and immunogenicity, and synergise with immunotherapy to improve antitumour outcomes.

Keywords

immunogenicity / JIB-04 / KDM4 / tumour-intrinsic innate sensing / type I interferons

References

[1] Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat Rev Cancer. 2021;21:298-312.

[2] Sharma P, Hu-Lieskovan S, Wargo JA, Ribas AP. Adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707-723.

[3] Haslam A, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open. 2019;2:e192535.

[4] Reck M, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823-1833.

[5] Zhang J, Huang D, Saw PE, Song E. Turning cold tumors hot: from molecular mechanisms to clinical applications. Trends Immunol. 2022;43:523-545.

[6] Kraehenbuehl L, Weng CH, Eghbali S, Wolchok JD, Merghoub T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat Rev Clin Oncol. 2022;19:37-50.

[7] Corrales L, Matson V, Flood B, Spranger S, Gajewski TF. Innate immune signaling and regulation in cancer immunotherapy. Cell Res. 2017;27:96-108.

[8] Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. Type I interferons in anticancer immunity. Nat Rev Immunol. 2015;15:405-414.

[9] Yu R, Zhu B, Chen D. Type I interferon-mediated tumor immunity and its role in immunotherapy. Cell Mol Life Sci. 2022;79:191.

[10] Crouse J, Kalinke U, Oxenius A. Regulation of antiviral T cell responses by type I interferons. Nat Rev Immunol. 2015;15:231-242.

[11] Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol. 2020;21:501-521.

[12] Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14:36-49.

[13] Onomoto K, Onoguchi K, Yoneyama M. Regulation of RIG-I-like receptor-mediated signaling: interaction between host and viral factors. Cell Mol Immunol. 2021;18:539-555.

[14] Sheng W, et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell. 2018;174:549-563.

[15] Dai E, et al. Epigenetic modulation of antitumor immunity for improved cancer immunotherapy. Mol Cancer. 2021;20:171.

[16] Cao J, Yan Q. Cancer epigenetics, tumor immunity, and immunotherapy. Trends Cancer. 2020;6:580-592.

[17] Yang J, Xu J, Wang W, Zhang B, Yu X, Shi S. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther. 2023;8:210.

[18] Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014;11:783-784.

[19] Boutet-Robinet E, Trouche D, Canitrot Y. Neutral comet assay. Bio-protocol. 2013;3:e915.

[20] Xie Z, Wang Z, Fan F, et al. Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation. Cell Discov. 2022;8:133.

[21] Wang L, Chang J, Varghese D, et al. A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth. Nat Commun. 2013;4:2035.

[22] Kwon J, Bakhoum SF. The cytosolic DNA-sensing cGAS-STING pathway in cancer. Cancer Discov. 2020;10:26-39.

[23] Matt S, Hofmann TG. The DNA damage-induced cell death response: a roadmap to kill cancer cells. Cell Mol Life Sci. 2016;73:2829-2850.

[24] Ivashkevich A, Redon CE, Nakamura AJ, Martin RF, Martin OA. Use of the gamma-H2AX assay to monitor DNA damage and repair in translational cancer research. Cancer Lett. 2012;327:123-133.

[25] Kroemer G, Galassi C, Zitvogel L, Galluzzi L. Immunogenic cell stress and death. Nat Immunol. 2022;23:487-500.

[26] Fucikova J, Kepp O, Kasikova L, et al. Detection of immunogenic cell death and its relevance for cancer therapy. Cell Death Dis. 2020;11:1013.

[27] Sulkowski PL, et al. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature. 2020;582:586-591.

[28] Yi M, Niu M, Xu L, Luo S, Wu K. Regulation of PD-L1 expression in the tumor microenvironment. J Hematol Oncol. 2021;14:10.

[29] Bald T, Landsberg J, Lopez-Ramos D, et al. Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation. Cancer Discov. 2014;4:674-687.

[30] Garcia-Diaz A, Shin DS, Moreno BH, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 2017;19:1189-1201.

[31] Wei Y, Zheng H, Bao N, et al. KDM6B overexpression activates innate immune signaling and impairs hematopoiesis in mice. Blood Adv. 2018;2:2491-2504.

[32] Wu L, Cao J, Cai WL, et al. KDM5 histone demethylases repress immune response via suppression of STING. PLoS Biol. 2018;16:e2006134.

[33] Schirrmacher V. From chemotherapy to biological therapy: a review of novel concepts to reduce the side effects of systemic cancer treatment (review). Int J Oncol. 2019;54:407-419.

[34] Kim MS, Cho HI, Yoon HJ, et al. JIB-04, a small molecule histone demethylase inhibitor, selectively targets colorectal cancer stem cells by inhibiting the Wnt/beta-catenin signaling pathway. Sci Rep. 2018;8:6611.

[35] Barrat FJ, Crow MK, Ivashkiv LB. Interferon target-gene expression and epigenomic signatures in health and disease. Nat Immunol. 2019;20:1574-1583.

[36] Kimura H. Histone modifications for human epigenome analysis. J Hum Genet. 2013;58:439-445.

[37] Sun D, Cao X, Wang C. Polycomb chromobox Cbx2 enhances antiviral innate immunity by promoting Jmjd3-mediated demethylation of H3K27 at the Ifnb promoter. Protein Cell. 2019;10:285-294.

[38] Chen LL, Xiong Y. Tumour metabolites hinder DNA repair. Nature. 2020;582:492-494.

RIGHTS & PERMISSIONS

2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.