Angioimmunoblastic T-cell lymphoma (AITL) is a kind of aggressive T-cell lymphoma with significant enrichment of non-malignant tumor microenvironment (TME) cells. However, the complexity of TME in AITL progression is poorly understood. We performed single-cell RNA-Seq (scRNA-seq) and imaging mass cytometry (IMC) analysis to compare the cellular composition and spatial architecture between relapsed/refractory AITL (RR-AITL) and newly diagnosed AITL (ND-AITL). Our results showed that the malignant T follicular helper (Tfh) cells showed significantly increased proliferation driven by transcriptional activation of YY1 in RR-AITL, which is markedly associated with the poor prognosis of AITL patients. The CD8+ T cell proportion and cytotoxicity decreased in RR-AITL TME, resulting from elevated expression of the inhibitory checkpoints such as PD-1, TIGIT, and CTLA4. Notably, the transcriptional pattern of B cells in RR-AITL showed an intermediate state of malignant transformation to B-cell-lymphoma, and contributed to immune evasion by highly expressing CD47 and PD-L1. Besides, compared to ND-AITL samples, myeloid-cells-centered spatial communities were more prevalent but showed reduced phagocytic activity and impaired antigen processing and presentation in RR-AITL TME. Furthermore, specific inhibitory ligand-receptor interactions, such as CLEC2D-KLRB1, CTLA4-CD86, and MIF-CD74, were exclusively identified in the RR-AITL TME. Our study provides a high-resolution characterization of the immunosuppression ecosystem and reveals the potential therapeutic targets for RR-AITL patients.
血管免疫母细胞性T细胞淋巴瘤（AITL）是一种侵袭性T细胞淋巴瘤，其肿瘤微环境（TME）中存在大量非恶性细胞的富集。然而，人们对AITL进展过程中TME的复杂性知之甚少。我们通过单细胞RNA测序（scRNA-seq）和成像质谱流式技术（IMC）分析，比较了复发/难治性AITL（RR-AITL）与初诊AITL（ND-AITL）的细胞组成和空间结构。结果显示，RR-AITL中恶性T滤泡辅助细胞（Tfh）的增殖显著增强，这由YY1的转录激活驱动，且与AITL患者的不良预后密切相关。RR-AITL的TME中CD8+ T细胞比例和细胞毒性功能下降，这源于PD-1、TIGIT和CTLA4等抑制性检查点表达的上调。值得注意的是，RR-AITL中B细胞的转录模式呈现出向B细胞淋巴瘤恶性转化的中间状态，并通过高表达CD47和PD-L1促进免疫逃逸。此外，与ND-AITL样本相比，RR-AITL的TME中以髓系细胞为中心的空间结构更为普遍，但其吞噬活性降低，抗原加工和呈递功能受损。更重要的是，我们在RR-AITL的TME中特异性地发现了CLEC2D-KLRB1、CTLA4-CD86和MIF-CD74等抑制性配体-受体相互作用。本研究对RR-AITL的免疫抑制生态系统进行了高分辨率解析，并揭示了潜在的治疗靶点。
肿瘤(癌症)患者之家