# Revealing tumor microenvironmental heterogeneity and prognostic value in angioimmunoblastic T-cell lymphoma via spatial transcriptome sequencing

## TL;DR

This study explores the tumor microenvironment in angioimmunoblastic T-cell lymphoma using spatial transcriptomics to reveal heterogeneity and its impact on prognosis.

## Contribution

The study introduces a detailed spatial transcriptomic analysis of AITL, revealing TME heterogeneity and its prognostic implications.

## Key findings

- Spatial transcriptome sequencing identified 14 clusters, including neoplastic clusters with B-cell shifts and myeloid cell enrichment.
- High CD40-CD40LG activity correlated with immune-suppressive genes, while low activity was linked to TAM enrichment and better survival.
- Trajectory analysis revealed distinct molecular evolution patterns within the AITL tumor microenvironment.

## Abstract

Angioimmunoblastic T-cell lymphoma (AITL) represents the second most prevalent subtype of peripheral T-cell lymphoma, characterized by a dismal prognosis. However, a systematic exploration of tumor microenvironment (TME) features and their prognostic significance in AITL remains notably deficient. To address this knowledge gap, we conducted spatial transcriptome sequencing (ST-SEQ) and whole-exome sequencing in four AITLs and two noncancerous lymph nodes for discovery purposes, complemented by immunohistochemistry analyses on 37 AITL cases for validation. We identified 14 ST clusters, including five neoplastic clusters, wherein a global shift in B-cell phenotypes and enrichment of myeloid cells were observed. These findings underscore a hallmark of exacerbated inflammation and immune dysregulation within the neoplastic TME. Among the 4 ST-sequenced AITLs, 3 expressed high CD40-CD40LG activity, accompanied by the upregulation of immune-suppressive-associated genes, such as CCL17 and PDCD1. Conversely, the remaining patient displayed an uncommon absence of CD40-CD40LG activity but harbored a phagocytosis-associated tumor-associated macrophage (TAM)-enriched TME, which correlated with significantly reduced relapse rates and longer event-free survival (EFS), highlighting the critical value of precise TME stratification in tailoring AITL therapeutic strategies. Finally, trajectory analysis unveiled a distinct trajectory of molecular evolution within this TME landscape. Collectively, our findings illuminate the heterogeneity and prognostic implications of the TME in AITL, providing a robust foundation for the rational design of targeted immunotherapeutic approaches. These insights may substantially advance the development of personalized treatment strategies for AITL patients.