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.
Highlights
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
The rationale is that some chemotherapeutic drugs turn non-immunogenic tumour cells to immunogenic, i.e. ICD13,16,61, to present antigens to dendritic cells (DCs) for recruiting T cells, while anti-PD-1/PD-L1 antibodies disrupt the negative immune-regulation and normalise the T cell functions[10,59]
We show that IOX1 enabled a paradigm of potent antibody-independent chemo-immunotherapy, where IOX1 effectively downregulated the PD-L1 expression of cancer cells and simultaneously stimulated the DOX-induced immunogenic cell death (ICD) through deactivation of the JMJD1A/β-catenin pathway (Fig. 1)
Summary
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. 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. How to efficiently induce ICD at low doses, in drug-resistant cancer cells, is critical to realise effective chemoimmunotherapy[22] Another key issue to improving the efficacy of the ICBimmunotherapy is to increase the PD-1/PD-L1 blockage efficiency, which is generally restricted due to antibodies’ poor tumour penetration. IOX1 effectively downregulates tumour PD-L1 expression in vitro and in vivo It inhibits cancer cell’s multidrug resistance and promotes intracellular DOX accumulation, greatly enhancing DOX-induced ICD. Because JMJD1A is overexpressed in many kinds of tumours[28] and promotes cancer cell progression and invasion by epigenetically activating transcription of β-catenin and its target genes[29], the readily available IOX1 provides a potent antibody-free chemo-immunotherapy paradigm for cancer treatment
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