LAG3 transcriptomic expression correlates with high levels of PD-1, PD-L1, PD-L2, and CTLA-4 checkpoints and with high tumor mutational burden across cancers.

Abstract

2561 Background: Lymphocyte Activation Gene 3 (LAG3) or CD223 is an immune checkpoint that can be found on various T cells: CD4+, CD8+, regulatory T cells (Tregs), natural killer T cells, natural killer cells, and plasmacytoid dendritic cells. The expression of LAG3 molecule acts to increase T-cell exhaustion, leading to decreased tumor killing as well as an increase in immune suppressive cytokine release. Many clinical trials of LAG3 inhibitors have had modest effects, but recent data suggests that the LAG3 antibody relatlimab together with nivolumab (anti-PD1) provided greater benefit than nivolumab alone in patients with melanoma. Methods: The RNA expression levels of 397 genes in various types of solid tumors from 514 patients seen at the UCSD Moores Cancer Center were analyzed at a CLIA-licensed laboratory, OmniSeq (https://www.omniseq.com/). Following removal of germline variants, synonymous variants, indels and SNVs with < 5% VAF, TMB is reported as mutations/megabase. Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) in a standardized manner to a reference population of 735 tumors spanning 35 histologies. Odds ratio for high LAG3 expression was calculated and Bonferroni corrected for multiple genes and cancer histologies with > 40 samples. Results: A total of 116 (22.6%) tumors had high LAG3 (≥75) across 32 different histologies. Cancers with the highest proportion of LAG3 were neuroendocrine (47%), uterine (43%), sarcoma (33%), breast (31%), ovarian (30%), pancreatic (24%), lung (20%), stomach (16%), and colorectal (15%). There was significant association for high LAG3 with high PD-L1 (adj P < 0.001), high PD-1 (adj P < 0.0014), high PD-L2 (adj P < 0.0014), high CTLA-4 (adj P < 0.0014), TMB ≥10 mt/mb (adj P = 0.0504). There was no significant association between histologies colorectal (adj P = 0.1834), breast (adj P = NS), ovarian (adj P = NS), pancreatic (adj P = NS), or gender (adj P = 0.272). Conclusions: High LAG3 was found in almost a quarter of tumor samples and significantly associated with other immune checkpoints with FDA-approved drugs. Ongoing studies combining LAG3 inhibitors and specific immune checkpoint inhibitors may yield more clinical benefit if individualized immunomic transcript interrogation is undertaken, rather than population-based approaches without employment of rationally combined agents matched to each patient’s cancer.