Exosomal PD-L1 promotes tumor growth through immune escape in non-small cell lung cancer

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.

Lung cancer: Immune suppressant protein promotes tumor growth

An immune suppressant protein expressed by non-small cell lung cancer cells (NSCLC) to facilitate tumor growth could be a valuable therapeutic target. NSCLC is often diagnosed at advanced stages, making treatment challenging. Therapies that inhibit an immune suppressant protein called programmed cell death ligand-1 (PD-L1) have shown promise for other cancers, but how PD-L1 interacts with host and tumor cells in NSCLC needs clarification. In experiments on human cell lines and mice, Jae Cheol Lee and Jin Kyung Rho at the University of Ulsan in Seoul, South Korea, and co-workers found that microvesicles (or ‘exosomes’) released by NSCLC cells carry PD-L1, which interacts with tumor-infiltrating immune cells, inhibiting their activity. The amount of PD-L1 in exosomes directly correlates with PD-L1 expression levels on tumor cell surfaces, providing a useful indication of disease activity.