PCSK9 regulates the efficacy of immune checkpoint therapy in lung cancer
Xiang Gao1,2, Ling Yi1, Chang Jiang3
1Cancer Research Center, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China.
Abstract:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) secreted by tumors was reported as a deleterious factor that led to the reduction of lymphocyte infiltration and the poorer efficacy of ICIs in vivo. This study aimed to explore whether PCSK9 expression in tumor tissue could predict the response of advanced non-small cell lung cancer (NSCLC) to anti-PD-1 immunotherapy and the synergistic antitumor effect of the combination of the PCSK9 inhibitor with the anti-CD137 agonist. One hundred fifteen advanced NSCLC patients who received anti-PD-1 immunotherapy were retrospectively studied with PCSK9 expression in baseline NSCLC tissues detected by immunohistochemistry (IHC). The mPFS of the PCSK9lo group was significantly longer than that of the PCSK9hi group [8.1 vs. 3.6 months, hazard ratio (HR): 3.450; 95% confidence interval (CI), 2.166-5.496]. A higher objective response rate (ORR) and a higher disease control rate (DCR) were observed in the PCSK9lo group than in the PCSK9hi group (54.4% vs. 34.5%, 94.7% vs. 65.5%). Reduction and marginal distribution of CD8+ T cells were observed in PCSK9hi NSCLC tissues. Tumor growth was retarded by the PCSK9 inhibitor and the anti-CD137 agonist alone in the Lewis lung carcinoma (LLC) mice model and further retarded by the PCSK9 inhibitor in combination with the CD137 agonist with long-term survival of the host mice with noticeable increases of CD8+ and GzmB+ CD8+ T cells and reduction of Tregs. Together, these results suggested that high PCSK9 expression in baseline tumor tissue was a deleterious factor for the efficacy of anti-PD-1 immunotherapy in advanced NSCLC patients. The PCSK9 inhibitor in combination with the anti-CD137 agonist could not only enhance the recruitment of CD8+ and GzmB+ CD8+ T cells but also deplete Tregs, which may be a novel therapeutic strategy for future research and clinical practice.
Insights
High PCSK9 expression in non-small cell lung cancer (NSCLC) predicts poor response to anti-PD-1 immunotherapy. Combining a PCSK9 inhibitor with an anti-CD137 agonist shows promise for enhancing anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) secreted by tumors is linked to reduced lymphocyte infiltration and diminished efficacy of immune checkpoint inhibitors (ICIs).
- The role of PCSK9 in predicting response to anti-PD-1 immunotherapy in advanced non-small cell lung cancer (NSCLC) requires further investigation.
- Exploring novel therapeutic strategies combining PCSK9 inhibition with immune agonists is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To determine if PCSK9 expression in tumor tissue can predict response to anti-PD-1 immunotherapy in advanced NSCLC patients.
- To evaluate the synergistic antitumor effect of combining a PCSK9 inhibitor with an anti-CD137 agonist.
- To investigate the impact of PCSK9 expression on immune cell infiltration and the efficacy of immunotherapy.
Main Methods:
- Retrospective analysis of 115 advanced NSCLC patients treated with anti-PD-1 immunotherapy.
- Quantification of PCSK9 expression in baseline NSCLC tissues using immunohistochemistry (IHC).
- Assessment of treatment response, including median progression-free survival (mPFS), objective response rate (ORR), and disease control rate (DCR).
- Evaluation of immune cell populations (CD8+ T cells, Tregs) in tumor tissues.
- Preclinical studies in a Lewis lung carcinoma (LLC) mice model using PCSK9 inhibitor and anti-CD137 agonist.
Main Results:
- Patients with low PCSK9 (PCSK9lo) expression had significantly longer mPFS (8.1 vs. 3.6 months) compared to those with high PCSK9 (PCSK9hi) expression.
- The PCSK9lo group exhibited higher ORR (54.4% vs. 34.5%) and DCR (94.7% vs. 65.5%) than the PCSK9hi group.
- PCSK9hi NSCLC tissues showed reduced CD8+ T cell infiltration.
- Combination therapy with PCSK9 inhibitor and anti-CD137 agonist demonstrated synergistic antitumor effects in mice, increasing CD8+ and GzmB+ CD8+ T cells and decreasing Tregs, leading to long-term survival.
Conclusions:
- High PCSK9 expression in baseline tumor tissue is a detrimental factor affecting the efficacy of anti-PD-1 immunotherapy in advanced NSCLC.
- The combination of a PCSK9 inhibitor and an anti-CD137 agonist enhances anti-tumor immunity by modulating T cell populations and depleting Tregs.
- This combination therapy represents a potential novel therapeutic strategy for NSCLC, warranting further research and clinical investigation.
