T细胞受体结构和克隆污染提供了有关周围T细胞淋巴瘤转化轨迹的洞察力
T-cell receptor architecture and clonal tiding provide insight into the transformation trajectory of peripheral T-cell lymphomas
影响因子:7.90000
分区:医学1区 Top / 血液学2区
发表日期:2025 Feb 01
作者:
Edith Willscher, Christoph Schultheiß, Lisa Paschold, Franziska Lea Schümann, Paul Schmidt-Barbo, Benjamin Thiele, Marcus Bauer, Claudia Wickenhauser, Thomas Weber, Mascha Binder
摘要
虽然T细胞淋巴瘤被归类为成熟的肿瘤，但新出现的证据表明，在T细胞成熟的早期阶段可能发生恶性转化。在这项研究中，我们在广泛的T细胞淋巴瘤中确定了克隆结构。我们的多维分析表明，这些淋巴瘤中的许多实际上确实从V（d）J重排之前的成熟阶段的未成熟淋巴T细胞前体出现，从而经历了分支的演变。因此，在单细胞分辨率下，我们观察到在选择性治疗压力下的可克隆膨胀。 T细胞受体的下一代测序表明，TRBV20-1基因段的高度使用是每位患者多个抗原受体重排的一部分。在分析的所有主要T细胞淋巴瘤亚型中发现TRBV20-1的优势。这表明该特定的V基因 - 独立于互补性区域3的配置 - 可能代表了恶性转化的驱动因素。总之，我们的数据表明，T细胞淋巴瘤是从未成熟的淋巴前体中得出的，并显示出相当大的肿瘤内异质性，这可能为这些难以治疗的癌症中的复发和抗性提供了基础。
Abstract
While T-cell lymphomas are classified as mature neoplasms, emerging evidence indicates that malignant transformation may occur at an earlier stage of T-cell maturation. In this study, we determined clonal architecture in a broad range of T-cell lymphomas. Our multidimensional profiling indicates that many of these lymphomas do in fact emerge from an immature lymphoid T-cell precursor at a maturation stage prior to V(D)J rearrangement that undergoes branching evolution. Consequently, at single-cell resolution we observed considerable clonal tiding under selective therapeutic pressure. T-cell receptor next-generation sequencing suggested a highly biased usage of TRBV20-1 gene segments as part of multiple antigen receptor rearrangements per patient. The predominance of TRBV20-1 was found across all major T-cell lymphoma subtypes analyzed. This suggested that this particular V gene - independently of complementarity-determining region 3 configuration - may represent a driver of malignant transformation. Together, our data indicate that T-cell lymphomas are derived from immature lymphoid precursors and display considerable intratumoral heterogeneity that may provide the basis for relapse and resistance in these hard-to-treat cancers.