PD-L1-EVs from esophageal squamous cell carcinoma decrease the ratio of circulating follicular helper T cells to follicular regulatory T cells and upregulate CTLA4 in the former, inhibiting follicular helper T cell differentiation by preventing the binding of CD28 to its ligands, leading to high expression of ICOS and activation of downstream PI3K100,101. This evidence concerns the gene ICOS and esophageal squamous cell carcinoma.