AbstractBackgroundLymphocyte activation gene 3 (LAG‐3) or CD223 is a transmembrane protein that serves as an immune checkpoint which attenuates T‐cell activation. Many clinical trials of LAG‐3 inhibitors have had modest effects, but recent data indicate that the LAG‐3 antibody relatlimab, together with nivolumab (anti‐PD‐1), provided greater benefit than nivolumab alone in patients with melanoma.MethodsIn this study, the RNA expression levels of 397 genes were assessed in 514 diverse cancers at a clinical‐grade laboratory (OmniSeq:https://www.omniseq.com/). Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0–100 percentile) using a reference population (735 tumors; 35 histologies).ResultsA total of 116 of 514 tumors (22.6%) had high LAG‐3 transcript expression (≥75 percentile rank). Cancers with the greatest proportion of high LAG‐3 transcripts were neuroendocrine (47% of patients) and uterine (42%); colorectal had among the lowest proportion of high LAG‐3 expression (15% of patients) (allp< 0.05 multivariate); 50% of melanomas were high LAG‐3 expressors. There was significant independent association between high LAG‐3 expression and high expression of other checkpoints, including programmed death‐ligand 1 (PD‐L1), PD‐1, and CTLA‐4, as well as high tumor mutational burden (TMB) ≥10 mutations/megabase, a marker for immunotherapy response (allp< 0.05 multivariate). However, within all tumor types, there was inter‐patient variability in LAG‐3 expression level.ConclusionsProspective studies are therefore needed to determine if high levels of the LAG‐3 checkpoint are responsible for resistance to anti‐PD‐1/PD‐L1 or anti‐CTLA‐4 antibodies. Furthermore, a precision/personalized immunotherapy approach may require interrogating individual tumor immunograms to match patients to the right combination of immunotherapeutic agents for their malignancy.