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Protein kinase Cι-driven macrophage infiltration mediates immunosuppression in non-small cell lung cancer
Shichuan Hu1, Zichen Zhao2, Jing Zhao3
1Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Abstract:
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer-related mortality. Immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death ligand 1 (PD-1/PD-L1) axis can induce durable tumor regression in a subset of NSCLC patients; however, most exhibit resistance to ICIs therapy. Here, we identify the protein kinase Cι (PKCι)) as a biomarker and critical mediator of poor ICIs responsiveness in NSCLC. High PKCι expression correlates with resistance to anti-PD-1 antibody (αPD1) therapy, whereas low PKCι expression are highly sensitive. PKCι-dependent resistance to αPD1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, PKCι regulated Yap1-dependent transcription of CCL7, which recruits TAMs and fosters an immunosuppressive microenvironment. In contrast, Overexpression of PKCι or CCL7 in PKCι-knockdown tumors restores TAMs infiltration and αPD1 resistance. Pharmacological inhibition of PKCι with auranofin (AF) reduces TAMs accumulation and promotes CD8+T cell infiltration by inhibiting the PKCι-Yap1-CCL7 axis. Combination therapy with AF and αPD1 triggers a CD8+T cell-dependent antitumor immune response, thereby controlling tumor growth in situ or subcutaneously. In summary, our study reveals a PKCι-mediated immunosuppressive pathway driving ICIs resistance and support PKCι inhibition as a promising strategy to enhance immunotherapy efficacy in NSCLC.
Insights
Protein kinase Cι (PKCι) drives resistance to immunotherapy in non-small cell lung cancer (NSCLC). Inhibiting PKCι with auranofin enhances anti-PD-1 therapy by reducing immunosuppressive cells and boosting T cell response.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality.
- Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis show efficacy in a subset of NSCLC patients, but resistance is common.
- Identifying mechanisms of ICI resistance is crucial for improving treatment outcomes.
Purpose of the Study:
- To identify biomarkers and mediators of resistance to anti-PD-1 (αPD1) therapy in NSCLC.
- To elucidate the molecular mechanisms underlying PKCι-mediated ICI resistance.
- To evaluate the therapeutic potential of inhibiting PKCι in combination with αPD1 therapy.
Main Methods:
- Correlative analysis of PKCι expression with αPD1 therapy response in NSCLC patients.
- Investigation of PKCι's role in regulating tumor microenvironment components, including tumor-associated macrophages (TAMs) and CD8+ T cells.
- Pharmacological inhibition of PKCι using auranofin (AF) in preclinical NSCLC models.
- Assessment of combination therapy with AF and αPD1 on tumor growth and immune response.
Main Results:
- High PKCι expression correlates with resistance to αPD1 therapy, while low expression indicates sensitivity.
- PKCι promotes an immunosuppressive tumor microenvironment by upregulating CCL7 via the Yap1 pathway, leading to increased TAMs and decreased CD8+ T cells.
- Pharmacological inhibition of PKCι with auranofin reduces TAMs, enhances CD8+ T cell infiltration, and synergizes with αPD1 therapy to control tumor growth.
Conclusions:
- PKCι is a critical mediator and biomarker of resistance to PD-1 blockade in NSCLC.
- The PKCι-Yap1-CCL7 axis promotes an immunosuppressive tumor microenvironment, driving ICI resistance.
- Inhibition of PKCι represents a promising therapeutic strategy to overcome ICI resistance and enhance immunotherapy efficacy in NSCLC.
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