Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy

• Published in: Nature communications Vol. 12; no. 1; pp. 2425 - 17
• Main Authors: Liu, Jing, Zhao, Zhihao, Qiu, Nasha, Zhou, Quan, Wang, Guowei, Jiang, Haiping, Piao, Ying, Zhou, Zhuxian, Tang, Jianbin, Shen, Youqing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/2; 13/21; 13/31; 14; 14/1; 14/19; 14/63; 38/88; 38/90; 59/5; 631/67/1059/2325; 631/67/1059/99; 631/67/1504/1885; 631/67/322; 631/67/580; 64/60; 8-Hydroxyquinoline; 82/80; Animals; Antibodies; Antibodies - immunology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; B7-H1 Antigen - metabolism; Cancer; Cell death; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - immunology; Chemotherapy; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - pharmacology; Glycoproteins; HCT116 Cells; Histones; Humanities and Social Sciences; Humans; Hydroxyquinoline; Hydroxyquinolines - administration & dosage; Hydroxyquinolines - chemistry; Hydroxyquinolines - pharmacology; Immune checkpoint; Immunogenicity; Immunological memory; Immunology; Immunosuppressive agents; Immunotherapy; Immunotherapy - methods; Infiltration; Inhibitors; Lung cancer; Lymphocytes; Lymphocytes T; MCF-7 Cells; Metastases; Mice; Mice, Inbred BALB C; Mice, Nude; Mortality; multidisciplinary; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - therapy; Neoplasms, Experimental - immunology; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - therapy; NIH 3T3 Cells; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Programmed Cell Death 1 Receptor - metabolism; Science; Science (multidisciplinary); T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor Burden - drug effects; Tumor Burden - immunology; Tumors; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22407-6

Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells’ P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy. Some chemotherapeutic drugs, such as doxorubicin, induce immunogenic cell death (ICD) and promote anti-tumor immune responses. Here the authors report that the histone demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX1) reduces the expression of PD-L1 in cancer cells and enhances doxorubicin-induced ICD, promoting T cell infiltration and reducing tumor growth in preclinical models.