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 EVs-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 (PFS). 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.

Regulation of Extracellular Vesicle-Mediated Immune Responses against Antigen-Specific Presentation

“…Therapy using EVs derived from cancer cells has gained popularity since it contains cancer antigens and induces a cancer antigen-specific immune response, which provides an anti-tumour effect [ 289 ]. Although inducing anti-tumour immunity using cancer-cell-derived EVs has been reported, the effect remains to be verified.…”

Harnessing Liquid Biopsies to Guide Immune Checkpoint Inhibitor Therapy

“…Importantly, an anti-PD-L1 blocking antibody significantly reversed the EV-mediated inhibition of CD8+ T-cell activation, suggesting a prognostic values PD-L1 + ve EVs in predicting the effectiveness of therapy detection, as well as a new strategy to enhance T-cell-mediated immunotherapy against SCLC cancers. When tested on another lung cancer cohort, the presence of EVs containing PD-L1 significantly correlated with the progression-free survival of patients on immunotherapy [ 126 ]. PD-L1 expressed on the EVs, not the soluble form of PD-L1, is also shown to be associated with disease progression in head and neck cancer [ 127 ].…”

“…In numerous studies, the presence of specific T cell subtypes, NK cells and other myeloid cells have been associated with the prediction of response to IO. Several clinical trials have also reported detecting PD-L1, PD-L2, and PD1 expression on either CTCs or circulating immune cells to predict the response to the IO [ 25 , 38 , 126 ]. However, the data are insufficient to clearly show the predictive power for IO.…”

Extracellular vesicles from non-neuroendocrine SCLC cells promote adhesion and survival of neuroendocrine SCLC cells

“…The copyright holder for this preprint this version posted October 13, 2022. ; https://doi.org/10.1101/2022.10.12.511984 doi: bioRxiv preprint immunosuppressive effects, inhibiting CD8+ T-cells by carrying PD-L1 22 . In the brain, microvascular endothelial cell-derived EVs can promote SCLC survival, potentially contributing to the high rate of SCLC metastasis to the brain 23 .…”