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One possibility is that high levels of cGMP induced by PDE5 blockade reduce the cytosolic Ca2+ concentration (46), leading to a reduction of the calcium-dependent protein kinase C activity (47) that in turn prevents up-regulation of IL-4R (48). The link between IL-4R and ARG1 in MDSCs is supported by recent data (29) demonstrating a direct correlation between ARG1 expression and IL-4R expression. ACT of tumor-primed CD8 T cells completely eradicated a preestablished C26GM tumor in the LysMCreIL-4R–/flox mice in which IL-4R expression has been deleted in neutrophils and macrophages, whereas no effect was seen in the control littermates (29). Our findings support these data by demonstrating that PDE5 blockade down-regulates IL-4R expression on tumor-infiltrating MDSCs (Fig. 6) and synergizes with the adoptive transfer of tumor-primed CD8+ T cells (Fig. 3 and Fig. 4). 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