Esophageal squamous cell carcinoma derived sEV-PDL1 exhausts CD8+T cells to promote immunosuppression.

Abstract

Esophageal squamous cell carcinoma (ESCC) is a common malignancy. Programmed death ligand 1 of small extracellular vesicles (sEV-PDL1) induce immune evasion and enhance tumor progression. However, the role of ESCC derived sEV-PDL1 in modulating CD8⁺T cell remains unclear. sEVs were isolated through differential centrifugation. CD8⁺T cells were isolated, stimulated and cultured with sEVs to evaluate the proportions, phenotypes, and functions by flow cytometry. Lentivirus infection and Crisper-Cas9 were used to constructed stable transgenic cell lines: Eca109-PDL1^kd and mEC25-PDL1^ko. The proportions of CD8⁺T cells in ESCC patients was lower than healthy donors (HD). Furthermore, a negative correlation between sEV-PDL1 and CD8⁺T cell was observed. sEV-PDL1 induced CD8⁺T cell exhaustion by reducing the expression levels of Ki67, Granzyme B (GrzmB), and interferon-γ (IFN-γ) both in vitro and in vivo. However, anti-PDL1 reversed the result. Our findings reveal that targeting sEV-PDL1 to rejuvenate CD8⁺T cell functions is one of the mechnisms a promising therapeutic strategy for ESCC.