Boosting anticancer immunity by blocking immune checkpoints such as the programmed death-1 (PD-1) or its ligand (PD-L1) is a breakthrough anticancer therapy. However, many cancer patients do not respond well to immune checkpoint blockades (ICBs) alone. Here we show that low-dose pharmacological immunoactivators (e.g., SN38, topotecan, sorafenib, etc.) notably downregulate PD-L1 and upregulate FOXO3 expression in various human and murine cancer cell lines. In a mouse tumor model, low-dose SN38 treatment markedly suppresses tumor growth, reduces PD-L1 expression, and enhances FOXO3 expression in primary tumor specimens. SN38 therapy engages the tumor-infiltrating mouse NK1.1/CD49b/NKG2D-positive natural killer (NK) cells to attack tumor cells by inducing mouse IFN-γ and granzyme-B secretion in the tumor microenvironment (TME) in vivo. SN38 treatment also promotes tumor cell apoptosis in the TME. SN38 treatment significantly decreases STAT3-pY705 and IL-6 protein levels; FOXO3 is essential for SN38-mediated PD-L1 downregulation. Collectively, these findings may contribute to future translational or clinical investigations tackling difficult-to-treat cancers with immune-activating medicines or combined with ICB immunotherapy.
Keywords: Cancer immunotherapy; FOXO3; PD-L1; SN38; antitumor immunity; immune checkpoint; immunoactivator; natural killer cell; sorafenib; topotecan.
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