Abstract
Lymphocyte-activation gene 3 (LAG-3) modulates the tumor microenvironment through immunosuppressive effects. Its associations with clinicopathologic parameters and prognostic significance in non-small-cell lung carcinomas remain unclear. We examined LAG-3 expression in 368 resected non-small-cell lung carcinomas (including 218 adenocarcinomas and 150 squamous-cell carcinomas) using tissue microarrays, with normalization to CD8(+) T-cell count (LAG-3/CD8 index), and correlated LAG-3, CD8, and LAG-3/CD8 index with clinicopathologic features, molecular status, and survival. LAG-3 expression in the immune cells (ranged 0.35-540.1 cells/mm²) was identified in 92% of non-small-cell lung carcinomas. In adenocarcinomas and squamous-cell carcinomas, LAG-3 expression correlated with CD8(+) T-cell count and PD-L1 expression. In adenocarcinomas, high LAG-3 expression (defined as >median) was additionally associated with smoking history, high T stage, aggressive pathologic features (solid-predominant histologic pattern, lymphovascular invasion, and nodal metastasis), and lack of EGFR mutation. In the entire resected tumor cohort and in adenocarcinomas, high LAG-3 and LAG-3/CD8 index were each associated with worse overall survival. In squamous-cell carcinomas, high CD8 was associated with better overall survival. In an exploratory analysis of pretreatment samples from advanced non-small-cell lung carcinoma patients treated with pembrolizumab, high CD8 was predictive of improved overall and progression-free survival, while high LAG-3, but not high LAG-3/CD8 index, was associated with improved progression-free survival. In conclusion, the clinicopathologic correlations and prognostic impact of LAG-3 in non-small-cell lung carcinoma are histotype-dependent, highlighting differences in the immune microenvironment between adenocarcinomas and squamous-cell carcinomas. The predictive impact of LAG-3 warrants further investigation.