Upregulation of extracellular matrix remodeling gene set drives progression and poor prognosis in angioimmunoblastic T-cell lymphoma.

Abstract Introduction Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive and heterogeneous peripheral T-cell lymphoma derived from follicular helper T cells (Tfh cells). Despite conventional chemotherapy, patient outcomes remain dismal, with a 5-year overall survival rate of only from 44% to 52% and progression-free survival of 32% [1]. Mounting evidence implicates the complex tumor microenvironment (TME) as a key driver of AITL pathogenesis and clinical heterogeneity. While interactions between immune cells within the tumor microenvironment have been elucidated, the role of extracellular matrix (ECM) remodeling in AITL pathogenesis remains unexplored [2]. To address this, we performed bulk and single-cell RNA sequencing on an AITL patient cohort, identifying an extracellular matrix (ECM) remodeling-associated gene signature with prognostic relevance in AITL. Method This study included frozen tumor tissues from 10 treatment-naïve AITL patients and fresh lymph node tissues from 3 additional treatment-naïve AITL patients, all diagnosed according to the 2022 World Health Organization criteria.Bulk RNA sequencing and single-cell transcriptome sequencing were employed to analyze these tissue samples to obtain prognostically relevant microenvironment characteristics and mechanisms of cell-cell communication. The comparative RNA sequencing dataset (GSE250050) was obtained from the Gene Expression Omnibus database. The comparative sc-RNA sequencing dataset was sourced from the study by Vitalii et al (https://doi.org/10.1101/2020.11.15.378125). Result Through Multi-omics analysis, this study revealed significant enrichment of ECM remodeling genes in AITL, correlating with poor prognosis. Single-cell RNA sequencing identified a unique tumor-associated stromal cell (TASC) population characterized by high expression of ECM remodeling-related genes. Compared to normal stroma, TASCs exhibited upregulated MMP2/9 (facilitating basement membrane degradation and metastasis, log2FC = 3.32/1.33), LAMA2/LAMB3 (potentially promoting extranodal extension, log2FC = 4.71/3.31), and COL1A1/2, TIMP1/2 (driving synthesis and stabilization of immunosuppressive type I collagen, log2FC = 8.72/7.66 and log2FC = 2.25/1.57), while downregulating COL4A1/2 (synthesizing type IV collagen, log2FC = -1.77/-1.22) and MMP1 (degrading type I collagen). Cell communication analysis revealed robust TASC-TFH cell interactions mediated by FN1-ITGA4 and COL1A2-CD44 pairs, potentially activating oncogenic PI3K/AKT and FAK/ERK pathways. These coordinated alterations demonstrate TASCs actively reshape the AITL ECM to create an immune-suppressive microenvironment conducive to invasion, and immune evasion.The strong association of TASC-derived ECM regulators such as MMP2 and COL1A2 with poor prognosis highlights their biomarker potential for risk stratification. While this study implicates TASCs as key orchestrators of the pathogenic AITL microenvironment and suggests targeting stromal-mediated ECM remodeling, further validation with larger cohorts and in vivo/in vitro experiments is needed. Conclusions This study identifies a unique tumor-associated stromal cell subpopulation, TASC, within the AITL microenvironment that drives ECM remodeling and engages in specific ligand-receptor interactions with Tfh cells. These findings establish TASCs as a critical mediator of AITL progression and poor prognosis, providing a novel prognostic biomarker and potential therapeutic target. References [1] Ricard, L., Cervera, P., Stocker, N., Corre, E., Van de Wyngaert, Z., Banet, A., Marjanovic, Z., Dulery, R., Bravetti, C., Joly, A.-C., et al. (2024). A combination of 5-azacytidine and nivolumab is a potentially effective rescue therapy in relapsed/refractory AITL. Front. Immunol. 15, 1410638. [2] Zhu, M., Li, N., Fan, L., Wu, R., Cao, L., Ren, Y., Lu, C., Zhang, L., Cai, Y., Shi, Y., et al. (2024). Single-cell transcriptomic and spatial analysis reveal the immunosuppressive microenvironment in relapsed/refractory angioimmunoblastic T-cell lymphoma. Blood Cancer J. 14, 1–18.