https://scholars.lib.ntu.edu.tw/handle/123456789/630872
Title: | SN-38, an active metabolite of irinotecan, enhances anti-PD-1 treatment efficacy in head and neck squamous cell carcinoma | Authors: | Lee, Yi-Mei Chen, Yu-Hsin DA-LIANG OU CHIA-LANG HSU Liu, Jia-Hua JENQ-YUH KO Hu, Mickey C-T CHING-TING TAN |
Keywords: | FoxO3a; NK cells; PD-1; PD-L1; head and neck squamous cell carcinoma; immune checkpoint inhibitor | Issue Date: | Apr-2023 | Publisher: | WILEY | Journal Volume: | 259 | Journal Issue: | 4 | Start page/Pages: | 428 | Source: | The Journal of pathology | Abstract: | Anti-programmed cell death 1 (anti-PD-1) therapy shows definite but modest activity in patients with advanced/metastatic head and neck squamous cell carcinoma (HNSCC). Preliminary evidence suggests that SN-38, an activated form of irinotecan that increases expression of the transcription factor FoxO3a, can suppress programmed cell death ligand-1 (PD-L1) expression in breast and ovarian tumor models. We analyzed the SN-38-mediated activation of natural killer cells in vitro and explored the efficacy of SN-38 in combination with anti-PD-1 for treatment in vivo. In vitro, SN-38 enhanced the expression of FoxO3a and reduced the expression of c-Myc and PD-L1 dose-dependently in tumor cells. Low-dose SN-38 increased interferon-γ secretion by NK cells and promoted NK cell-mediated cytotoxicity in tumor cells. In vivo studies revealed that at non-cytotoxic drug concentrations, SN-38 significantly enhanced anti-PD-1 activity in suppressing murine tumor growth. We found increased NK cell and CD8+ T-cell infiltration in post-treatment tumors. RNA-seq analysis indicated that SN-38 increased the enrichment of immune cells and biological function genes related to the immune responses. SN-38 is a potentially beneficial adjunct to checkpoint inhibitor therapy in HNSCC. Further studies exploring its mechanism of action and possible applications are necessary. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/630872 | ISSN: | 0022-3417 | DOI: | 10.1002/path.6055 |
Appears in Collections: | 腫瘤醫學研究所 |
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