LAG-3 transcriptomic expression patterns across malignancies: Implications for precision immunotherapeutics.

Area of Science:

• Immunology and Oncology
• Cancer Genomics and Transcriptomics

Background:

• Lymphocyte Activation Gene 3 (LAG-3), also known as CD223, is an immune checkpoint protein that regulates T-cell activation.
• While LAG-3 inhibitors have shown modest clinical effects, recent studies combining LAG-3 blockade with PD-1 inhibitors demonstrate enhanced efficacy in melanoma.

Purpose of the Study:

• To assess the RNA expression levels of LAG-3 across a diverse range of 514 human cancers.
• To investigate the association between high LAG-3 expression and other immune checkpoint markers and tumor mutational burden (TMB).

Main Methods:

• RNA expression of 397 genes was analyzed in 514 diverse cancer samples using clinical-grade laboratory services.
• Transcript abundance was normalized and ranked using a reference population of 735 tumors across 35 histologies.
• High LAG-3 expression was defined as a percentile rank of ≥75.

Main Results:

• High LAG-3 transcript expression (≥75th percentile) was observed in 22.6% (116/514) of the assessed tumors.
• Neuroendocrine (47%) and uterine (42%) cancers showed the highest proportions of high LAG-3 expression, while colorectal cancers had lower expression (15%).
• High LAG-3 expression was significantly associated with elevated levels of other immune checkpoints (PD-L1, PD-1, CTLA-4) and high TMB (≥10 mutations/megabase).

Conclusions:

• The study identifies specific cancer types with high LAG-3 expression, warranting further investigation into its role in resistance to current immunotherapies.
• Inter-patient variability in LAG-3 expression highlights the need for personalized immunotherapy strategies.
• Tailoring combination immunotherapies based on individual tumor immunograms, including LAG-3 status, may optimize treatment outcomes.