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<p>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 <i>CD40</i>-<i>CD40LG</i> activity, accompanied by the upregulation of immune-suppressive-associated genes, such as <i>CCL17</i> and <i>PDCD1</i>. Conversely, the remaining patient displayed an uncommon absence of <i>CD40</i>-<i>CD40LG</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月9日

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  • Xiang Zhang,
  • Yong Sun,
  • Duo Wu,
  • Fang Yu,
  • Hanjin Yang,
  • Xingnong Ye,
  • Juying Wei,
  • Xuewu Zhang,
  • Yanan Zhu,
  • Yunfei Lv,
  • Zijing Xu,
  • Yuxiang Chen,
  • Hongyan Tong,
  • Jie Jin,
  • Xiaofei Ye,
  • Wenjuan Yu

摘要

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.