Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA
Wenxin Zhang1, Xiaohui Pan1, Yanjun Xu2
1Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Abstract:
Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8+ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.
Insights
Higher plasma mevalonate levels correlate with better response to anti-programmed death-(ligand)1 therapy in non-small cell lung cancer. Mevalonate supplementation enhances anti-tumor immunity and PD-L1 expression, suggesting its potential as an immunosensitizer.
Area of Science:
- Immunology
- Metabolic pathways
- Oncology
Background:
- Mevalonate metabolism is crucial for tumor progression but its role in immune evasion and checkpoint modulation is unclear.
- Non-small cell lung cancer (NSCLC) treatment efficacy can be limited by immune evasion mechanisms.
Purpose of the Study:
- To investigate the role of mevalonate metabolism in immune checkpoint modulation in NSCLC.
- To determine the correlation between plasma mevalonate levels and response to anti-programmed death-(ligand)1 (PD-(L)1) therapy.
Main Methods:
- Analysis of plasma mevalonate levels and correlation with progression-free survival and overall survival in NSCLC patients.
- In vitro studies using NSCLC cell lines to assess the effect of mevalonate on programmed death-ligand 1 (PD-L1) expression.
- Investigation of the molecular mechanisms underlying mevalonate-induced PD-L1 regulation, including mRNA stability and protein binding.
- In vivo studies to evaluate the impact of mevalonate supplementation on anti-PD-(L)1 therapy efficacy and T cell responses.
Main Results:
- Higher plasma mevalonate levels were associated with improved outcomes in NSCLC patients treated with anti-PD-(L)1 therapy.
- Mevalonate supplementation upregulated PD-L1 expression in NSCLC cells by enhancing CD274 mRNA stability via HuR binding.
- Mevalonate addition improved anti-tumor effects of anti-PD-(L)1 in vivo, increasing CD8+ T cell infiltration and cytotoxic function.
Conclusions:
- Plasma mevalonate levels are a potential biomarker for predicting response to anti-PD-(L)1 therapy in NSCLC.
- Mevalonate supplementation can act as an immunosensitizer, enhancing the efficacy of immune checkpoint blockade therapy in NSCLC.
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