ABSTRACT
Objective:To explore the markers predicting the efficacy of anti-programmed death receptor-1 (PD-1)/PD-1 ligand (PD-L1) immunotherapy for non-small cell lung cancer (NSCLC) and analyze their relationships with the tumor immune microenvironment.Methods:(1) Gene expression profile data and relevant clinical data of 55 NSCLC patients receiving anti-PD-1/PD-L1 monotherapy from two independent clinical cohorts were downloaded from the GEO database. Genes associated with progression-free survival (PFS) were screened using univariate Cox regression analysis. (2) Twenty-six pathological tissue specimens of NSCLC patients who received anti-PD-1/PD-L1 monotherapy in the Cancer Hospital of Chinese Academy of Medical Sciences (CICAMS) from April 2016 to August 2019 prior to the screening of genes were selected to verify the predictive value of the screened genes using immunohistochemistry. (3) The relationship between efficacy predictive markers and PD-L1 and infiltrating immune cells in the tumor immune microenvironment was analyzed using NSCLC gene expression profile downloaded from the TCGA database.Results:Univariate Cox regression analysis revealed that only T-Cell Surface Glycoprotein CD3 Gamma Chain (CD3G) was a risk predictive gene for PFS in NSCLC patients in both clinical cohorts of the GEO database (GSE93157: P = 0.049; GSE136961: P = 0.034). Further Kaplan-Meier survival curves showed that PFS was significantly prolonged in the high CD3G expression group ( P = 0.012). The results of survival analysis in the CICAMS clinical cohort also demonstrated that NSCLC patients with high CD3G expression had a better prognosis after receiving anti-PD-1/PD-L1 monotherapy ( P = 0.001) compared with those with low CD3G expression. Univariate and multivariate Cox regression analyses also showed that CD3G was an independent predictor of PFS (univariate: P = 0.002; multivariate: P = 0.001). The tumor immune microenvironment analysis showed that CD3G was positively correlated with PD-L1 expression (lung adenocarcinoma: r = 0.44, P < 0.001; lung squamous cell carcinoma: r = 0.37, P < 0.001) and the infiltration level of CD8 + T cells (lung adenocarcinoma: r = 0.13, P = 0.002; lung squamous cell carcinoma: r = 0.70, P < 0.001). CD3G was also positively correlated with the expression of CD8 + T cell chemokines CCL5, CXCL9, CXCL10 and CXCL11. Conclusion:Patients with NSCLC with high CD3G expression have greater clinical benefits after anti-PD-1/PD-L1 monotherapy compared with those with low CD3G expression. CD3G can be used as a potential marker to predict the efficacy of immunotherapy for NSCLC.