Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antibodies / immunology
-
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
-
B7-H1 Antigen / antagonists & inhibitors
-
B7-H1 Antigen / immunology
-
B7-H1 Antigen / metabolism
-
Cell Line, Tumor
-
Cell Survival / drug effects
-
Cell Survival / immunology
-
Doxorubicin / administration & dosage
-
Doxorubicin / pharmacology*
-
HCT116 Cells
-
Humans
-
Hydroxyquinolines / administration & dosage
-
Hydroxyquinolines / chemistry
-
Hydroxyquinolines / pharmacology*
-
Immunotherapy / methods*
-
MCF-7 Cells
-
Mice
-
Mice, Inbred BALB C
-
Mice, Nude
-
NIH 3T3 Cells
-
Neoplasms / immunology
-
Neoplasms / metabolism
-
Neoplasms / therapy*
-
Neoplasms, Experimental / immunology
-
Neoplasms, Experimental / metabolism
-
Neoplasms, Experimental / therapy
-
Programmed Cell Death 1 Receptor / antagonists & inhibitors
-
Programmed Cell Death 1 Receptor / immunology
-
Programmed Cell Death 1 Receptor / metabolism
-
T-Lymphocytes / drug effects*
-
T-Lymphocytes / immunology
-
T-Lymphocytes / metabolism
-
Tumor Burden / drug effects
-
Tumor Burden / immunology
Substances
-
Antibodies
-
B7-H1 Antigen
-
CD274 protein, human
-
Hydroxyquinolines
-
Programmed Cell Death 1 Receptor
-
Doxorubicin
-
5-carboxy-8-hydroxyquinoline