Genomic and immunologic correlates of LAG-3 expression in cancer

Abstract

Immune checkpoint blockade leads to unprecedented responses in many cancers. Although currently available agents mostly target the PD-1 and CTLA-4 pathways, agents targeting the immune checkpoint protein LAG-3 are under active clinical development, and early clinical data show that <i>LAG-3</i> expression is a biomarker of response to LAG-3 blockade. To determine which cancers may benefit most from LAG-3 blockade, we performed a pan-cancer analysis of The Cancer Genome Atlas dataset to identify genomic and immunologic correlates of <i>LAG-3</i> expression. High mutation burden, and expression of exogenous virus (EBV, HPV) or endogenous retrovirus (<i>ERV3-2</i>), were associated with overexpression of <i>LAG-3</i> in multiple cancers. Although CD8⁺ T-cell marker (<i>CD8A</i>) and <i>LAG-3</i> were strongly co-expressed with each other and with <i>PD-L1</i> in most cancers, there were three notable exceptions: HPV+ head-neck squamous cell cancer, renal cell cancer, and glioblastoma. These results may have important implications for guiding development clinical trials of LAG-3 blockade.