Abstract
Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 treatment has yielded clinical benefits in several types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that exosomes derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T-cell activity and promoting tumor growth. The abundance of PD-L1 on exosomes represented the quantity of PD-L1 expression on cell surfaces. Exosomes containing PD-L1 inhibited interferon-gamma (IFN-γ) secretion by Jurkat T cells. IFN-γ secretion was restored by PD-L1 knockout or masking on the exosomes. Both forced expression of PD-L1 on cells without PD-L1 and treatment with exosomes containing PD-L1 enhanced tumor growth in vivo. PD-L1 was present on exosomes isolated from the plasma of patients with non-small cell lung cancer, and its abundance in exosomes was correlated with PD-L1 positivity in tumor tissues. Exosomes can impair immune functions by reducing cytokine production and inducing apoptosis in CD8+ T cells. Our findings indicate that tumor-derived exosomes expressing PD-L1 may be an important mediator of tumor immune escape.
Highlights
Lung cancer is the leading cause of cancer death worldwide[1]
These results show that PD-L1 is present in exosomes secreted by cancer cells and that its abundance in these exosomes reflects its expression on the cancer cells
The same group of researchers revealed that the PD-L1 levels on exosomes are associated with disease progression in patients with head and neck cancer, suggesting that circulating PD-L1 exosomes are a useful marker of disease activity[38]
Summary
Lung cancer is the leading cause of cancer death worldwide[1]. Despite advances in the understanding of cancer biology and the development of new therapeutic agents, most cases of lung cancer are diagnosed at an advanced stage and have a poor prognosis, non-small cell lung cancer (NSCLC) cases. NSCLC was originally not considered to be an immunotherapy-responsive tumor type. That outlook has since changed, because of the recent improvement in survival rates due to the use of immune checkpoint inhibitors such as anti-programmed cell death protein-1 (anti-PD-1) or anti-programmed cell death protein ligand-1 (anti-PD-L1) monoclonal antibodies[3,4]. The PD-1/PD-L1 pathway is a mechanism of adaptive immune escape used by tumor cells in response to endogenous antitumor activity. When PD-L1 expressed on tumor cells binds to PD-1 receptors
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