J Cancer 2019; 10(26):6703-6710. doi:10.7150/jca.34469

Research Paper

Combination of PD-L1 expression and NLR as prognostic marker in patients with surgically resected non-small cell lung cancer

Xinyue Wang1,2,3,4, Lianjing Cao5, Shouying Li1,2,3,4, Fan Wang1,2,3,4, Dingzhi Huang1,2,3,4, Richeng Jiang1,2,3,4✉

1. Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer
2. Key Laboratory of Cancer Prevention and Therapy, Tianjin
3. Tianjin's Clinical Research Center for Cancer
4. Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin 300060, PR China
5. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China

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Wang X, Cao L, Li S, Wang F, Huang D, Jiang R. Combination of PD-L1 expression and NLR as prognostic marker in patients with surgically resected non-small cell lung cancer. J Cancer 2019; 10(26):6703-6710. doi:10.7150/jca.34469. Available from http://www.jcancer.org/v10p6703.htm

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Background: In recent years, great improvement has been made in immunotherapies for non-small cell lung cancer (NSCLC). Current data have suggested that Programmed cell death ligand 1 (PD-L1) expression might not be an ideal marker for patient selection in isolation. Evidence has been increasing that alternative markers, such as neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation response (SIR) previously associated with outcomes in a variety of cancers including NSCLC, might be a predictor for patient selection and the response to therapy. No reports have examined the prognostic value of combination of PD-L1 expression and inflammatory markers such as NLR in NSCLC. This retrospective study explores the relationship between NLR and PD-L1 expression in NSCLC as well as the prognostic value of combination of PD-L1 expression and NLR.

Method: We evaluated tumor PD-L1 expression in 235 surgically resected NSCLC cases by immunohistochemical analysis. Carcinoma cells showing membranous staining for PD-L1 were considered PD-L1-positive cells (Figure 1). Cases with ≥1% tumor membrane staining were considered PD-L1-positive. The association of clinicopathological characteristics with PD-L1 expression was assessed by univariate and multivariate analyses. Moreover, univariate and multivariate analyses were performed to evaluate the predictive impact of PD-L1 expression and other factors on disease-free survival (DFS) and overall survival (OS).

Result: PD-L1 protein expression was elevated in 34.0% of patients at cut-off value of 1%. Univariate analyses showed that PD-L1 expression was significantly higher in men (χ2 =5.226, P=0.030), heavy smokers (χ2 =18.650, P<0.001), and patients with squamous cell carcinoma (χ2 =4.036, P=0.045). No correlations were noted between PD-L1 expression and age, EGFR mutation status or clinical stage. No significant correlations between PD-L1 protein expression and NLR were found. Multivariate logistic regression revealed that smoking index ≥400 was independent predictor of PD-L1 expression (odds ratio [OR], 3.375; P < 0.001). The results of univariate survival analyses showed that clinical stage (log-rank χ2 =7.876, P=0.019) was associated with DFS. Smoking index (log-rank χ2 =4.832, P=0.028), clinical stage (log-rank χ2 =7.582, P=0.023) and adjuvant treatment (log-rank χ2 =5.440, P=0.020) were significantly associated with OS. Neither PD-L1 expression nor NLR was found to be associated with DFS or OS. Of interest, when patients were divided in two groups according to combined PD-L1/NLR: patients with PD-L1+/ high NLR as Group 1, other patients as Group 2, Group 1 had significantly shorter DFS as well as OS than Group 2 (DFS: log-rank χ2 =5.231, P=0.022, Figure 2A; OS: log-rank χ2 =4.742, P=0.029, Figure 2B). In the multivariate analysis, Cox proportional hazards regression models showed that, PD-L1+/ high NLR was associated with a significantly shorter DFS and OS (hazard ratio [HR], 1.394, P=0.040; HR, 1.442, P=0.042, respectively). Stratified analysis showed that the prognostic value of combined PD-L1/NLR can only be observed in cases without epidermal growth factor receptor (EGFR) mutations (DFS: log-rank χ2 =5.593, P=0.018, Figure 2C, OS: log-rank χ2 =9.323, P=0.002, Figure 2D). In EGFR mutation subgroup, combination of PD-L1 expression and NLR has no relationship with DFS or OS.

Conclusion: We found that combination of PD-L1 expression and NLR may be a promising prognostic indicator, and may also be a good marker for tumor recurrence, especially in the patients with wild-type EGFR.

Keywords: neutrophil-lymphocyte ratio, programmed death ligand-1, immunohistochemical analysis, prognostic marker, non-small cell lung cancer