LAG-3 Transcriptomic Expression Patterns Across Malignancies: Implications for Precision Immunotherapeutics

Background: Lymphocyte 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.

Methods: In 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).

Results: A 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) (all p < 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 (all p < 0.05 multivariate). However, within all tumor types, there was inter-patient variability in LAG-3 expression level.

Conclusions: Prospective 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.