Effect of PD-L1 expression on the efficacy of pemetrexed-based chemotherapy in patients with advanced lung adenocarcinoma and its mechanism

Abstract

Background and purpose: The expression of programmed death ligand-1 (PD-L1) in lung cancer not only is the most important biomarker for predicting the efficacy of programmed death-1 (PD-1)/PD-L1 inhibitors, but also may affect the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) targeted therapy. However, there are currently few reports in the relevant literature on whether the expression of PD-L1 in lung cancer can affect the efficacy of chemotherapy in patients with lung adenocarcinoma. This study mainly explored the effect of PD-L1 expression in lung adenocarcinoma on the efficacy of pemetrexed-based chemotherapy and its underlying mechanism. Methods: From Oct. 2015 to Dec. 2018, 185 eligible lung adenocarcinoma patients treated in Department of Pathology, The General Hospital of Western Theater Command PLA were enrolled. The expressions of PD-L1 and thymidylate synthase (TS), a molecule predicting the efficacy of pemetrexed-based chemotherapy, were detected by immunohistochemistry. The survival curve of patients was drawn by Kaplan-Meier method. The log-rank test and COX regression model were used to analyze the clinicopathological factors affecting the patients’ progression-free survival (PFS) and overall survival (OS). The log-rank test was used to analyze the effects of PD-L1 and TS expressions on the patients’ PFS and OS. Spearman rank correlation test was used to analyze the correlation between PD-L1 expression and TS expression in lung cancer tissues. Western blot and real-time fluorescent quantitative polymerase chain reaction (RTFQ-PCR) were used to detect the protein and mRNA expressions of PD-L1 and TS in 6 types of lung adenocarcinoma cell lines. The Pearson correlation test was used to analyze the correlation between PD-L1 and TS at protein expression level and mRNA expression level. Results: Among 51 patients with advanced lung adenocarcinoma who received pemetrexed-based chemotherapy as first-line treatment, the objective response rate (ORR) of the PD-L1 positive group was 20.0%, and the disease control rate (DCR) was 60.0%. There was no significant difference compared with the PD-L1 negative group (ORR: 20.0% vs 35.5%, χ 2 =1.404, P=0.236; DCR: 60.0% vs 80.6%, χ 2 =2.602, P=0.107). The median PFS (mPFS) of patients with negative expression of PD-L1 was significantly better than that of patients with positive expression of PD-L1 (mPFS: 5.6 months vs 4.1 months, log-rank=5.406, P=0.020), and there was no significant difference in median OS (mOS) between them (mOS: 15.9 months vs 12.7 months, log-rank=0.525, P=0.469). Univariate analysis found that the positive expressions of PD-L1 and TS were risk factors for PFS ［PD-L1 negative vs positive: HR=2.002 (1.100-3.645), P=0.023; TS negative vs positive: HR=2.205 (1.367-4.587), P=0.003］. Multivariate analysis found that TS positive expression was an independent risk factor for PFS ［TS negative vs positive: HR=3.245 (1.091-9.652), P=0.034］. Among the 51 patients with advanced lung adenocarcinoma who received pemetrexed-based chemotherapy as the first-line treatment, the expression of PD-L1 in cancer tissues was significantly positively correlated with the expression of TS (r s =0.691, P<0.001). We further compared the subjects after expanding to 185 patients of lung adenocarcinoma with different tumor stages and first-line treatments, and the expressions of PD-L1 and TS in cancer tissues still showed a significant positive correlation (r s =0.588, P<0.001). In 6 types of lung cancer cell lines including A549 and H1437, the expressions of PD-L1 and TS at the protein level and mRNA level were significantly positively correlated (protein expression level: r s =0.899, P<0.05; mRNA expression level: r s =0.861, P<0.05). Conclusion: In patients with advanced lung adenocarcinoma who received pemetrexed as the first-line chemotherapy, the PFS of patients with positive PD-L1 expression was significantly shorter than that of patients with negative PD-L1 expression, suggesting that PD-L1 expression may be used as a potential biomarker for predicting the efficacy of pemetrexed-based chemotherapy. There is a significant correlation between the expressions of PD-L1 and TS in both lung adenocarcinoma tissues and lung cancer cell lines, which may be one of the potential reasons why the expression of PD-L1 affects the efficacy of pemetrexed-based chemotherapy.

Keywords

• lung adenocarcinoma| pd-l1|thymidylate synthase| pemetrexed