Targeting lysosomal protease CTSL promotes anti-tumor immunity and sensitizes HNSCC to PD-1 blockade by stabilizing...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Cathepsin L (CTSL) is present in head and neck squamous cell carcinoma (HNSCC), but its function in immune evasion is not well understood.
• Understanding CTSL's role is crucial for developing effective cancer immunotherapies.

Purpose of the Study:

• To elucidate the mechanism by which CTSL contributes to immune escape in HNSCC.
• To evaluate the therapeutic potential of targeting CTSL in HNSCC models and its correlation with clinical outcomes.

Main Methods:

• Investigated the interaction between CTSL and PDK1, focusing on ubiquitination and stabilization.
• Assessed the impact of CTSL on AKT phosphorylation and PD-L1 expression in tumor cells.
• Evaluated tumor growth suppression in xenograft and immunocompetent mouse models, both as a single agent and in combination with anti-PD-1 therapy.
• Correlated CTSL expression with PD-L1 levels, CD8+ T-cell infiltration, and patient prognosis in HNSCC cohorts.

Main Results:

• CTSL directly binds PDK1, inhibiting its ubiquitination and stabilizing it, which sustains AKT phosphorylation and upregulates PD-L1 on tumor cells.
• CTSL exhibits a non-proteolytic scaffolding function that suppresses tumor growth in preclinical models.
• The combination of CTSL inhibition and anti-PD-1 therapy demonstrated synergistic effects on tumor suppression.
• High CTSL expression in HNSCC patients correlated with increased PD-L1, reduced CD8+ T-cell infiltration, and poorer prognosis.

Conclusions:

• CTSL acts as a key mediator of PD-L1-dependent immune evasion in HNSCC via the CTSL-PDK1-AKT pathway.
• CTSL inhibition represents a promising therapeutic strategy for HNSCC.
• CTSL may serve as a predictive biomarker for response to PD-1/PD-L1 blockade therapies in HNSCC.