Single-cell transcriptomic mapping of immune heterogeneity across angioimmunoblastic T-cell lymphoma subtypes

Relapse and treatment resistance remain critical obstacles in the clinical management of angioimmunoblastic T-cell lymphoma (AITL), limiting the success of current therapeutic strategies. Therefore, a comprehensive characterization of the tumor microenvironment (TME) in AITL is essential to enhance treatment efficacy. This study analyzed samples from 68 patients with AITL, stratified into three molecular subtypes based on immunoglobulin (IG) gene rearrangement and flow cytometry results. Utilizing single-cell RNA sequencing, the TME was profiled across subtypes A, B, and C, sampling multiple disease sites including the bone marrow, lymph nodes, and peripheral blood. Our findings revealed subtype-specific variations in cellular composition and transcriptional programs within the TME. Unlike other subtypes, subtype C was associated with a pronounced immunosuppressive environment at diagnosis and relapse. Additionally, it exhibited an enhanced response to Epstein-Barr virus infection, consistent with upregulated CD70 expression at relapse. Through the analysis of cellular communication networks, CD70, programmed cell death 1 (PDCD1), and inducible T cell costimulator (ICOS) were identified as promising immunotherapeutic targets in AITL. Finally, we delineated distinct cellular proportions and gene expression signatures characteristic of each subtype, providing a foundation for the development of tailored therapeutic interventions for patients with AITL.