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Published on: May 24, 2024
Targeting XIAP-coordinated PKC signaling resensitizes PD-1-refractory tumors for rechallenge
Jupeng Yuan1,2, Yujiao Ma1,2, Ying Dong1,2
1Department of Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250000, People's Republic of China.
Summary
Protein kinase C (PKC) activity predicts non-small cell lung cancer outcomes. Inhibiting PKC overcomes resistance to PD-1 blockade by promoting cell death and T cell responses, offering a new strategy for refractory cancers.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune-checkpoint blockade (ICB) targeting PD-1/PD-L1 has transformed cancer therapy.
- Primary and acquired resistance limit ICB efficacy, necessitating alternative strategies.
- The mechanisms underlying ICB resistance and effective rechallenge remain unclear.
Purpose of the Study:
- To identify biomarkers and therapeutic targets for overcoming anti-PD-1 resistance in non-small cell lung cancer (NSCLC).
- To elucidate the molecular mechanisms by which protein kinase C (PKC) inhibition impacts anti-PD-1 refractory tumors.
- To evaluate PKC inhibition as a salvage strategy in combination with other immunotherapies.
Main Methods:
- Assessed substrate-based PKC activity as a prognostic biomarker in NSCLC.
- Investigated the effects of pan-PKC inhibition on anti-PD-1-refractory tumor models.
- Analyzed downstream signaling pathways including Caspase-3/GSDME, GSK3β, PD-L1 degradation, CCL4-CCR5, XIAP, PTEN, and Wnt/β-Catenin-ATF3.
- Evaluated combination therapies with anti-CTLA-4 and anti-PD-1/PD-L1 in resistant models.
Main Results:
- PKC activity serves as a prognostic biomarker in NSCLC.
- Pan-PKC inhibition overcomes anti-PD-1 resistance by inducing immunogenic pyroptotic cell death.
- PKC inhibition promotes tumor-intrinsic PD-L1 degradation and enhances CD8+ T cell recruitment and function via CCL4-CCR5 signaling.
- PKC blockade destabilizes XIAP, stabilizes PTEN, and suppresses Wnt/β-Catenin-ATF3 signaling, driving CCL4 expression.
- PKC inhibition synergizes better with anti-CTLA-4 than anti-PD-1/PD-L1 in resistant models, reducing regulatory T cells and enhancing CD8+ T cell function.
Conclusions:
- The PKC-XIAP axis is a critical regulator of immune resistance in cancer.
- PKC inhibition represents a promising therapeutic target to overcome ICB resistance.
- Combined PKC inhibition and anti-CTLA-4 therapy offers a potential salvage strategy for ICB-refractory cancers.
