FOXO3-dependent suppression of PD-L1 promotes anticancer immune responses via activation of natural killer cells

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Immune checkpoint blockades (ICBs) targeting PD-1/PD-L1 are vital anticancer therapies.
• Many patients exhibit limited response to ICBs alone, necessitating novel therapeutic strategies.
• Enhancing endogenous anticancer immunity is crucial for overcoming treatment resistance.

Purpose of the Study:

• To investigate the potential of low-dose pharmacological immunoactivators to enhance anticancer immunity.
• To explore the mechanisms by which these agents modulate immune checkpoints and cellular responses.
• To evaluate the efficacy of low-dose SN38 in preclinical cancer models.

Main Methods:

• Treatment of human and murine cancer cell lines with low-dose immunoactivators (SN38, topotecan, sorafenib).
• Assessment of PD-L1 and FOXO3 expression levels.
• Tumor growth suppression studies in a mouse model using low-dose SN38.
• Analysis of natural killer (NK) cell activity, cytokine secretion (IFN-γ, granzyme-B), and apoptosis in the tumor microenvironment (TME).
• Evaluation of STAT3 and IL-6 levels.

Main Results:

• Low-dose immunoactivators downregulate PD-L1 and upregulate FOXO3 expression in cancer cells.
• SN38 treatment significantly suppresses tumor growth in vivo.
• SN38 enhances NK cell-mediated cytotoxicity via IFN-γ and granzyme-B secretion.
• SN38 promotes tumor cell apoptosis and reduces STAT3-pY705 and IL-6 levels.
• FOXO3 is critical for SN38-induced PD-L1 downregulation.

Conclusions:

• Low-dose immunoactivators, exemplified by SN38, can effectively boost anticancer immunity.
• SN38 modulates the TME by activating NK cells and promoting tumor cell death.
• FOXO3 plays a key role in the mechanism of PD-L1 downregulation by SN38.
• These findings support the development of novel therapeutic strategies combining immunoactivators with ICBs for challenging cancers.