Unraveling Cathepsin S regulation in interleukin-7-mediated anti-tumor immunity reveals its targeting potential against oral cancer.
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.
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.
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.
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.
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.
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.
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.
Authors
Chang Chang, Chen Chen, Chen Chen, Hsiao Hsiao, Chen Chen, Chen Chen, Liu Liu, Chen Chen, Liu Liu, Wu Wu, Chu Chu, Qiu Qiu, Chiang Chiang, Hsieh Hsieh, Hsueh Hsueh, Hsiao Hsiao, Shen Shen, Chang Chang, Chang Chang
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