Single-cell transcriptomic and spatial analysis reveal the immunosuppressive microenvironment in relapsed/refractory angioimmunoblastic T-cell lymphoma
Mengyan Zhu, Ning Li, Lei Fan, Rongrong Wu, Lei Cao, Yimin Ren, Chuanyang Lu, Lishen Zhang, Yun Cai, Yuzhu Shi, Zihan Lin, Xueying Lü, Jia‐yan Leng, Shiyang Zhong, Xianglin Hu, Bin Huang, Renhong Huang, Wanting Zhou, Diru Yao, Lingxiang Wu, Wei Wu, Quanzhong Liu, Peng Xia, Ruize Chen, Wenyu Shi, Ruohan Zhang, Sali Lv, Chunling Wang, Liang Yu, Jianyong Li, Qianghu Wang, Kening Li, Hui Jin
Abstract
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.