Accumulating evidence suggests that EVs are commonly found in blood, urine, saliva, tears, and many other body fluids 9– 11. These membrane-bound vesicular structures contain substantial amounts of biologically active proteins, lipids, and nucleic acids acquired from their parental cells, which they can transport to other cells 8. Despite notable and durable responses in patients, basic and clinical studies are still required to determine the exact mechanism of PD-1/PD-L1 immunotherapy, including the roles of many cofactors, and the relationship between the efficacy of PD-1/PD-L1 immunotherapy and the appropriate selection of patients.Įxtracellular vesicles (EVs), also known as microparticles, are small, membrane-enclosed sacs thought to be shed from the surface of healthy or damaged cells under conditions such as cell activation, growth, and apoptosis 6, 7. When PD-L1 expressed on tumor cells binds to PD-1 receptors on immune cells, the interaction leads to the inhibition of CD8 + cytotoxic T lymphocyte proliferation, survival, and effector function, thereby inducing the apoptosis of tumor-infiltrating T cells 5. In tumor biology, the PD-1/PD-L1 pathway is a mechanism of adaptive immune escape used by tumor cells in response to endogenous antitumor activity. That outlook has since changed, however, 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. NSCLC was originally not considered to be an immunotherapy-responsive tumor type. Although those targeted therapies have improved survival rates among patients with NSCLC, the prognosis of NSCLC remains poor, and new therapeutic approaches are required. For the past 10 years, considerable research has focused on the inhibition of specific targets, such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement 2. 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, particularly non-small cell lung cancer (NSCLC) cases. Lung cancer is the leading cause of cancer death worldwide 1. Our findings indicate that tumor-derived exosomes expressing PD-L1 may be an important mediator of tumor immune escape. Exosomes can impair immune functions by reducing cytokine production and inducing apoptosis in CD8 + T cells. 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. Both forced expression of PD-L1 on cells without PD-L1 and treatment with exosomes containing PD-L1 enhanced tumor growth in vivo. IFN-γ secretion was restored by PD-L1 knockout or masking on the exosomes. Exosomes containing PD-L1 inhibited interferon-gamma (IFN-γ) secretion by Jurkat T cells. The abundance of PD-L1 on exosomes represented the quantity of PD-L1 expression on cell surfaces. 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.
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. Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway blockade is a promising new cancer therapy.
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