Expression and Clinical Implications of LAG-3 in Small Cell Lung Cancer

The PD-L1 immune checkpoint inhibitors (ICIs) improve the survival in small cell lung cancer (SCLC), yet only a small subset experiences durable responses, possibly due to less than 20% of SCLC expressing PD-L1 > 1% of tumor cells. Evaluating the expression of checkpoint molecules in SCLC may identify molecules beyond PD-L1 that are amenable to ICIs. We firstly evaluated 28 immune checkpoint molecules via RNA-seq data in the Cancer Cell Line Encyclopedia database. Next, our in-house proteogenomic dataset and other publicly available datasets, including microarray data, RNA-seq data, and scRNA-seq data from tumor specimens, were enrolled. IMpower133 and Roper et al. datasets were employed to evaluate LAG-3 as a predictive marker of immunotherapy efficacy in SCLC. Finally, Immunohistochemistry was performed to verify LAG-3 expression in SCLC. LAG-3 exhibited higher expression in SCLC cell lines than in lung adenocarcinoma, lung squamous cell carcinoma, and melanoma. Analysis of SCLC tumor and paired normal samples revealed the highest overexpression of LAG-3 in SCLC tumors among compiled checkpoint molecules. Higher LAG-3 expression correlated with longer overall survival and served as an independent favorable prognostic factor. Furthermore, higher LAG-3 expression was associated with increased MHC-I expression, immune cell infiltration, and certain immune checkpoints' expression. Increased LAG-3 expression correlated with ICI benefit in SCLC patients. scRNA-seq analysis revealed that LAG-3 was primarily expressed in the tumor cells and T cells, and LAG-3 expression was higher than that of PD-1, CD274, and CTLA-4 on the CD8⁺ T cells. LAG-3 might serve as a potential biomarker in SCLC.