COX-2-related tumor immune microenvironment in non-small cell lung cancer: a novel signature to predict hot and cold tumor

BACKGROUND: At present, non-small cell lung cancer (NSCLC) remains a great threat to the health of people worldwide. Immune checkpoint inhibitors (ICIs) have shown positive results in the treatment of advanced NSCLC. However, the treatment response of ICIs is not stable and unpredictable. We used a bioinformatics analysis to determine a novel signature to diagnose the hot and cold tumor in NSCLC which may guide the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) therapeutic strategy. METHODS: The RNA-seq dataset and clinical data of 485 lung adenocarcinoma (LUAD) and 473 lung squamous cell carcinoma (LUSC) samples from The Cancer Genome Atlas (TCGA) database. Tumor infiltrating immune cells was calculated by CIBERSORT algorithm and ConsensusClusterPlus was used to classify the hot and cold tumor. Least absolute shrinkage and selection operator (LASSO) regression, Support Vector Machine (SVM) and Gaussian Mixture Model (GMM) were performed to determine the diagnostic area under curve (AUC) of novel signature of ICIs treatment. Overall survival (OS) analysis was based on the Kaplan-Meier statistical method. RESULTS: In this study, we found that the expression of PD-1/PD-L1 is associated with COX2 (PTGS2) expression. We identified novel signatures [STMN3, KIRREL1, SH2D3C, VCL, PDCD1, CD274, PTGS2, combined diagnostic (AUC) =0.838], in order to diagnose the hot and cold tumor subtype to indicate the treatment response of PD-1/PD-L1 inhibitor in NSCLC. Furthermore, we found that in hot tumor subtype, high PDCD1 expression group had worse OS than low PDCD1 expression group (P=0.047); high SH2D3C expression group had worse OS than low SH2D3C expression group either (P=0.003). SH2D3C was correlated to PD-1 expression in NSCLC samples (R=0.49, P<0.001). We speculated that SH2D3C likely plays a crucial role in PD-1-related immunotherapy in NSCLC patients. Pathway enrichment showed that the focal adhesion (P=0.005) and actin cytoskeleton (P=0.022) pathways were associated with OS. CONCLUSIONS: This study aimed to identify the classification of hot and cold tumors, and develop a novel signature to predict the ICI treatments response for PD-1/PD-L1 high expression NSCLC patients.