Extracellular vesicles containing PD-L1 contribute to CD8+ T-cell immune suppression and predict poor outcomes in small cell lung cancer

Abstract

Programmed death ligand-1 (PD-L1) is expressed on the surface of tumor cells and binds to programmed cell death protein-1 (PD1) on the surface of T cells, leading to cancer immune evasion via inhibition of T-cell function. One of the characteristics of small cell lung cancer (SCLC) is its ineffective anti-tumor immune response and highly immunosuppressive status in the tumor microenvironment. SCLC cells have been shown to generate extracellular vesicles (EVs), which may play an important role in tumor progression. We thus hypothesized that SCLC EVs may be important mediators of immunosuppression and that PD-L1 could play a role. Herein, we showed that PD-L1 was expressed on the surface of SCLC-derived EVs, with the potential to directly bind to PD1. Experimentally, we further showed that EVs secreted by SCLC cells can inhibit CD8+ T-cell activation and cytokine production in vitro in response to T-cell receptor stimulation. Importantly, an anti-PD-L1 blocking antibody significantly reversed the EV-mediated inhibition of CD8+ T-cell activation. Furthermore, we performed a retrospective study of patients with SCLC to determine the prognostic value of PD-L1 harvested from plasm circulating EVs. The results showed that EVs containing PD-L1 was an independent prognostic factor and significantly correlated with progression-free survival. Together, these results indicate that EVs containing PD-L1 can be served as a diagnostic biomarker for predicting the effectiveness of therapy, as well as a new strategy to enhance T-cell-mediated immunotherapy against SCLC cancers.

Keywords: CD8+ T cell; clinical significance; extracellular vesicles; immune suppression; programmed death-ligand 1; small cell lung cancer.