TP53 mutation is associated with selective upregulation of LAG3 independent of immune infiltration and antigen-presentation signatures in WHO grade 4 glioma

Abstract

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.