Youji Uemae, Shunichiro Miki, Erika Yamada, Alexander Zaboronok, Tadao Ohno, and Eiichi Ishikawa TP53 mutation is associated with selective upregulation of LAG3 independent of immune infiltration and antigen-presentation signatures in WHO grade 4 glioma. Neuro-Oncology Advances,2026;8:vdag233. https://doi.org/10.1093/noajnl/vdag233 |
Abstract
Background. Lymphocyte activation gene 3 (LAG3) has emerged as a clinically actionable immune checkpoint target
in oncology, but its molecular determinants in glioma remain poorly characterized. We aimed to determine whether
TP53 mutation is associated with LAG3 expression, whether this is selective among immune checkpoint genes, and
whether it persists after adjustment for transcriptomic immune scores.
Methods. We analyzed gene expression and mutation data from the Genomic Data Commons (GDC), incorporating
three datasets (TCGA, CPTAC, HCMI) into a GDC discovery cohort of WHO grade 4 glioma (n = 442). An independent
Glioma Longitudinal Analysis (GLASS) dataset served as a validation cohort (n = 79). LAG3 and 6 additional checkpoint
genes were compared between TP53-mutant and wild-type tumors using Wilcoxon rank-sum tests and adjusted
linear regression with transcriptomic immune scores as covariates.
Results. TP53 mutation was consistently associated with elevated LAG3 expression in the GDC cohort (median
difference = +0.288 log2(TPM + 1), Cliff’s δ = 0.289, P = 7.13 × 10–7) and replicated in the GLASS cohort (δ = 0.395,
P = .005). Among 7 checkpoint genes, only LAG3 showed significant TP53-associated upregulation after
Benjamini–Hochberg correction in both cohorts. The TP53 regression coefficient was unchanged after immune score
adjustment, and TP53 status was not associated with any immune score (all P ≥ .67). Adjustment for tumor purity
and proliferation-related Hallmark programs partially attenuated but did not abolish the association.
Conclusions. TP53 mutation is associated with selective, immune context-independent LAG3 upregulation in grade
4 glioma, supporting TP53 mutation as a candidate stratifier for LAG3-targeted immunotherapy and motivating
mechanistic studies.
