Identification and Validation of Immune-Related Long Non-Coding RNA Signature for Predicting Immunotherapeutic Response and Prognosis in NSCLC Patients Treated With Immunotherapy

BACKGROUND: Numerous studies have reported that long non-coding RNAs (lncRNAs) play important roles in immune-related pathways in cancer. However, immune-related lncRNAs and their roles in predicting immunotherapeutic response and prognosis of non-small cell lung cancer (NSCLC) patients treated with immunotherapy remain largely unexplored. METHODS: Transcriptomic data from NSCLC patients were used to identify novel lncRNAs by a custom pipeline. ImmuCellAI was utilized to calculate the infiltration score of immune cells. The marker genes of immunotherapeutic response-related (ITR)-immune cells were used to identify immune-related (IR)-lncRNAs. A co-expression network was constructed to determine their functions. LASSO and multivariate Cox analyses were performed on the training set to construct an immunotherapeutic response and immune-related (ITIR)-lncRNA signature for predicting the immunotherapeutic response and prognosis of NSCLC. Four independent datasets involving NSCLC and melanoma patients were used to validate the ITIR-lncRNA signature. RESULTS: In total, 7,693 novel lncRNAs were identified for NSCLC. By comparing responders with non-responders, 154 ITR-lncRNAs were identified. Based on the correlation between the marker genes of ITR-immune cells and lncRNAs, 39 ITIR-lncRNAs were identified. A co-expression network was constructed and the potential functions of 38 ITIR-lncRNAs were annotated, most of which were related to immune/inflammatory-related pathways. Single-cell RNA-seq analysis was performed to confirm the functional prediction results of an ITIR-lncRNA, LINC01272. Four-ITIR-lncRNA signature was identified and verified for predicting the immunotherapeutic response and prognosis of NSCLC. Compared with non-responders, responders had a lower risk score in both NSCLC datasets (P<0.05). NSCLC patients in the high-risk group had significantly shorter PFS/OS time than those in the low-risk group in the training and testing sets (P<0.05). The AUC value was 1 of responsiveness in the training set. In melanoma validation datasets, patients in the high-risk group also had significantly shorter OS/PFS time than those in the low-risk group (P<0.05). The ITIR-lncRNA signature was an independent prognostic factor (P<0.001). CONCLUSION: Thousands of novel lncRNAs in NSCLC were identified and characterized. In total, 39 ITIR-lncRNAs were identified, 38 of which were functionally annotated. Four ITIR-lncRNAs were identified as a novel ITIR-lncRNA signature for predicting the immunotherapeutic response and prognosis in NSCLC patients treated with immunotherapy.