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SN-38, an active metabolite of irinotecan, enhances anti-PD1 treatment efficacy in head and neck squamous cell carcinoma

ABSTRACT: Anti-programmed cell death 1 (PD-1) therapy shows definite but modest activity in patients with advanced/metastatic HNSCC. Preliminary evidence suggests that SN-38, an activated form of irinotecan that activates the transcription factor FoxO3a, may suppress the expression of PD-L1 in breast and ovarian tumor models. Here, we explore the efficacy of SN-38 in combination with anti-PD1 for HNSCC treatment. In vitro, SN-38 enhances FoxO3a expression and reduces the expression of PD-L1 dose-dependently in HNSCC cells. Low dose SN-38 increases interferon- excretion by natural killer (NK) cells and promotes NK cell-mediated cytotoxicity of tumor cells. In vivo studies reveal that, at non-cytotoxic drug concentrations, SN-38 significantly enhances anti-PD-1 activity in suppressing murine tumor growth. An increased infiltration of CD8+ T cells and NK cells was found in the post-treatment tumors. RNA-seq analysis confirms that SN-38 promotes the enrichment of immune cells and biological function genes related to the immune response became abundant in SN-38 and anti-PD1 treated tumors. Thus, SN-38 is a potentially beneficial adjunct to checkpoint inhibitor therapy in HNSCC. Further studies to explore its mechanism of action and possible application are mandatory.

ORGANISM(S): Mus musculus

PROVIDER: GSE222450 | GEO | 2023/01/11

REPOSITORIES: GEO

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