Multi-omics analysis identifies GAA as an independent poor prognostic biomarker and candidate therapeutic target in angioimmunoblastic T-cell lymphoma.

BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma with poor clinical outcomes and limited therapeutic options. The contribution of metabolic reprogramming and immune microenvironmental alterations to AITL progression remains insufficiently defined. METHODS: We conducted integrative transcriptomic and proteomic analyses of AITL samples compared with reactive lymphoid hyperplasia to identify molecules associated with treatment response and prognosis. Immune infiltration and pathway enrichment analyses were performed, and findings were validated in independent GEO cohorts (GSE19069 and GSE58445). Key protein expression was confirmed by immunohistochemistry and multiplex immunofluorescence. RESULTS: Differential expression analyses revealed that lysosomal alpha-glucosidase (GAA), a key enzyme involved in glycogen metabolism, was significantly upregulated at both the RNA and protein levels in patients who failed to respond to standard chemotherapy. Elevated GAA expression was associated with inferior overall survival in multivariate analysis. Immunohistochemistry staining and multiplex immunofluorescence further confirmed the spatial expression pattern of GAA in AITL tissues. Immune deconvolution and pathway enrichment analyses suggested that GAA-high tumors exhibited increased CD8+ T-cell infiltration accompanied by transcriptional features of T-cell exhaustion, as well as transcriptionally inferred metabolic alterations characterized by enhanced glycolysis-related signatures and reduced oxidative phosphorylation-related signatures. These findings were further validated in an independent AITL cohort from the GEO database. CONCLUSIONS: Our study identifies GAA as a candidate biomarker associated with adverse clinical outcomes, immune microenvironmental features, and metabolic pathway alterations in AITL, highlighting glycogen metabolism as a previously underexplored biological axis and a potential therapeutic vulnerability warranting further functional investigation.