A Novel Mechanism of Tumour Cell Drug Resistance Induced by the Programmed Death-Ligand 1 (PD-L1) Immune Checkpoint
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Immune checkpoints are regulators of the immune system that are critical for self-tolerance and prevention of autoimmunity. The programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint is often co-opted by tumour cells to escape the immune system. Whereas most studies on the PD-1/PD-L1 immune checkpoint focus on mechanisms leading to inactivation of immune effectors, we have shown that binding of PD-1 to PD-L1 on the surface of tumour cells leads to activation of oncogenic pathways as well as resistance to the chemotherapeutic agent doxorubicin in tumour cells. Development of drug resistance is responsible for treatment failure in over 90% of patients with metastatic cancer. Autophagy is a well-established mechanism of drug resistance in cancer cells. Hence, we hypothesized that PD-1/PD-L1 signalling induces drug resistance in tumor cells by up-regulating autophagic pathways. Immunoblot analysis demonstrated that exposure of human breast cancer cells to recombinant PD-1 (rPD-1) resulted in a time-dependent increase in LC3-II as well as Beclin1 protein levels, two important mediators of autophagy. 4T1 mammary carcinomas from mice treated with rPD-1 also showed increased levels of LC3-II protein levels. Moreover, imaging of breast cancer cells expressing GFP-tagged LC3 revealed a time-dependent increase in autophagosome formation following administration of rPD-1. Inhibition of autophagy using chloroquine prevented drug resistance induced by PD-1/PD-L1 signalling. Furthermore, results revealed that exposure of breast cancer cells to rPD-1 resulted in increased extracellular signal-related kinase (ERK) phosphorylation, and that ERK phosphorylation is required for PD-1/PD-L1 induced autophagy. These studies provide a rationale for the use of PD-1/PD-L1 immune checkpoint blockers and autophagy inhibitors as potential chemosensitizers in cancer therapy.