Scholarlink

Background <p>Immunomodulatory agents benefit a small percentage of patients with oral cancer (OC), a subset of head and neck cancer. Cathepsin S (CTSS), a lysosomal protease, has been frequently associated with tumor immunity. This study aimed to investigate the mechanism by which tumor CTSS affects anti-tumor immunity through the regulation of interleukin-7 (IL-7) to overcome this obstacle.</p> Methods <p>OC patients’ samples were used to disclose the correlation among CTSS and CD8<sup>+</sup> T cell infiltration levels. The cytokine array was used to investigate the effect of CTSS on the secretion of cytokine/chemokines. We utilized various cell biology experiments to investigate the molecular mechanism of CTSS that mediates IL-7 secretion in OC cell lines, including fluorescence resonance energy transfer, immunogold-labeled transmission electron microscopy, IL-7-enzyme-linked immunosorbent assay, immunofluorescence staining, and pull-down assay. Two syngeneic OC mice models were utilized to investigate the anti-cancer effects and the tumor immunity modulation effects of RJW-58, a CTSS activity inhibitor, and the combination with the anti-PD-1 antibody.</p> Results <p>CTSS expression was inversely correlated with CD8<sup>+</sup> T-cell infiltration in clinical samples. In vivo and in vitro studies using a mouse OC tumor model showed that CTSS-knockdown inhibited tumor growth and enhanced CD8<sup>+</sup> T cell proliferation. These results were counteracted by co-treatment with anti-CD8 or anti-IL-7 antibodies. CTSS inhibition also remodeled the memory CD8<sup>+</sup> T cell subsets within tumor tissues in vivo. Mechanistically, CTSS inhibited IL-7 secretion by disrupting its intracellular transport route. This was achieved by recognizing the intracellular domain of the IL-7 receptor (IL-7R), which bound IL-7 in granular vesicles. RJW-58 enhanced IL-7 secretion and exerted an anti-tumor effect. RJW-58 enhanced the therapeutic effect of the anti-PD-1 antibody in syngeneic mouse models.</p> Conclusion <p>The findings indicate that CTSS negatively regulates IL-7 secretion by interacting with IL-7R. The CTSS-targeting strategy has the potential to reinvigorate IL-7-directed anti-tumor T cell immunity and enhance the therapeutic effect of the anti-PD-1 antibody.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Unraveling Cathepsin S regulation in interleukin-7-mediated anti-tumor immunity reveals its targeting potential against oral cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月24日

查看全文
  • Yung-Chieh Chang,
  • Szu-Jung Chen,
  • Shang-Hung Chen,
  • Sheng-Yen Hsiao,
  • Li-Hsien Chen,
  • Chung-Hsing Chen,
  • Chan-Chuan Liu,
  • Ya-Wen Chen,
  • Ko-Jiunn Liu,
  • Shang-Yin Wu,
  • Jui-Mei Chu,
  • Li-Ying Qiu,
  • Wei-Fan Chiang,
  • Hsing-Pang Hsieh,
  • Wen-Yun Hsueh,
  • Jenn-Ren Hsiao,
  • Meng-Ru Shen,
  • Jang-Yang Chang,
  • Kwang-Yu Chang

摘要

Background

Immunomodulatory agents benefit a small percentage of patients with oral cancer (OC), a subset of head and neck cancer. Cathepsin S (CTSS), a lysosomal protease, has been frequently associated with tumor immunity. This study aimed to investigate the mechanism by which tumor CTSS affects anti-tumor immunity through the regulation of interleukin-7 (IL-7) to overcome this obstacle.

Methods

OC patients’ samples were used to disclose the correlation among CTSS and CD8+ T cell infiltration levels. The cytokine array was used to investigate the effect of CTSS on the secretion of cytokine/chemokines. We utilized various cell biology experiments to investigate the molecular mechanism of CTSS that mediates IL-7 secretion in OC cell lines, including fluorescence resonance energy transfer, immunogold-labeled transmission electron microscopy, IL-7-enzyme-linked immunosorbent assay, immunofluorescence staining, and pull-down assay. Two syngeneic OC mice models were utilized to investigate the anti-cancer effects and the tumor immunity modulation effects of RJW-58, a CTSS activity inhibitor, and the combination with the anti-PD-1 antibody.

Results

CTSS expression was inversely correlated with CD8+ T-cell infiltration in clinical samples. In vivo and in vitro studies using a mouse OC tumor model showed that CTSS-knockdown inhibited tumor growth and enhanced CD8+ T cell proliferation. These results were counteracted by co-treatment with anti-CD8 or anti-IL-7 antibodies. CTSS inhibition also remodeled the memory CD8+ T cell subsets within tumor tissues in vivo. Mechanistically, CTSS inhibited IL-7 secretion by disrupting its intracellular transport route. This was achieved by recognizing the intracellular domain of the IL-7 receptor (IL-7R), which bound IL-7 in granular vesicles. RJW-58 enhanced IL-7 secretion and exerted an anti-tumor effect. RJW-58 enhanced the therapeutic effect of the anti-PD-1 antibody in syngeneic mouse models.

Conclusion

The findings indicate that CTSS negatively regulates IL-7 secretion by interacting with IL-7R. The CTSS-targeting strategy has the potential to reinvigorate IL-7-directed anti-tumor T cell immunity and enhance the therapeutic effect of the anti-PD-1 antibody.

Graphical Abstract