LAG-3 transcriptomic expression correlates linearly with other checkpoints, but not with clinical outcomes.
American journal of cancer research(2024)
摘要
Immune checkpoint inhibitors have revolutionized the treatment landscape for patients with cancer. Multi-omics, including next-generation DNA and RNA sequencing, have enabled the identification of exploitable targets and the evaluation of immune mediator expression. There is one FDA-approved LAG-3 inhibitor and multiple in clinical trials for numerous cancers. We analyzed LAG-3 transcriptomic expression among 514 patients with diverse cancers, including 489 patients with clinical annotation for their advanced malignancies. Transcriptomic LAG-3 expression was highly variable between histologies/cancer types and within the same histology/cancer type. LAG-3 RNA levels correlated linearly, albeit weakly, with high RNA levels of other checkpoints, including PD-L1 (Pearson's R2 = 0.21 (P < 0.001)), PD-1 (R2 = 0.24 (P < 0.001)) and CTLA-4 (R2 = 0.19 (P < 0.001)); when examined for Spearman correlation, significance did not change. LAG-3 expression (dichotomized at ≥ 75th (high) versus < 75th (moderate/low) RNA percentile level) was not a prognostic factor for overall survival (OS) in 272 immunotherapy-naïve patients with advanced/metastatic disease (Kaplan Meier analysis; P = 0.54). High LAG-3 levels correlated with longer OS after anti-PD-1/PD-L1-based checkpoint blockade (univariate (P = 0.003), but not multivariate analysis (hazard ratio, 95% confidence interval = 0.80 (0.46-1.40) (P = 0.44))); correlation with longer progression-free survival showed a weak univariate trend (P = 0.13). Taken together, these results suggest that high LAG-3 levels in and of themselves do not predict resistance to anti-PD-1/PD-L1 checkpoint blockade. Even so, since LAG-3 is often co-expressed with PD-1, PD-L1 and/or CTLA-4, selecting patients for combinations of checkpoint blockade based on immunomic co-expression patterns is a strategy that merits exploration.
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