Lucas Fabienne, Pennell Michael, Huang Ying, Benson Don M, Efebera Yvonne A, Chaudhry Maria, Hughes Tiffany, Woyach Jennifer A, Byrd John C, Zhang Suohui, Jones Desiree, Guan Xiangnan, Burd Christin E, Rosko Ashley E
Division of Hematology, The Ohio State University, Columbus, Ohio.
College of Public Health, Division of Biostatistics, The Ohio State University, Columbus, Ohio.
Biol Blood Marrow Transplant. 2020 Jan;26(1):7-15. doi: 10.1016/j.bbmt.2019.08.009. Epub 2019 Aug 21.
Autologous stem cell transplant (ASCT) is the standard of care for patients with multiple myeloma (MM). The clinical significance of peripheral blood T lymphocyte (PBTL) immunologic changes associated with ASCT is poorly understood. Here we evaluated T cell transcriptional messenger RNA profiles and immunophenotypes to correlate immunologic senescence, exhaustion, and anergy with clinical endpoints in a cohort of patients with MM undergoing ASCT. ASCT induced global transcriptional T cell changes and altered molecular levels of markers of T cell subtypes, T cell activation, and exhaustion. These included reduced CD4/CD8 ratio, skewing toward the Th1 subset, reduced expression of costimulatory receptors CD27 and CD28, heightened T cell activation, and increased expression of immune modulatory molecules LAG3 and PD1. Multicolor flow cytometry experiments confirmed altered circulating CD4 and CD8 subsets and skewing toward differentiated effector cells. Moreover, ASCT promoted an exhausted immunophenotype in CD3CD4 subsets and a senescent immunophenotype in CD3CD8 subsets. Subset-specific altered expression was also seen for surface molecules with immunomodulatory function. ASCT affected soluble levels of molecules with immunomodulatory function by increasing plasma HVEM and TIM3. High molecular LAG3 level was associated with inferior event-free survival post-ASCT (hazard ratio = 5.44; confidence interval, 1.92 to 15.46; P = .001; adjusted P [controlling for false discovery rate] = .038). Using a comprehensive evaluation of PBTLs on a molecular and phenotypic level, we have identified that ASCT induces global T cell alterations with CD4 and CD8 subset-specific changes. Moreover, LAG3 emerged as an early biomarker of adverse events post-ASCT. These findings will support the development of treatment strategies targeting immune defects in MM to augment or restore T cell responses.
自体干细胞移植（ASCT）是多发性骨髓瘤（MM）患者的标准治疗方法。与ASCT相关的外周血T淋巴细胞（PBTL）免疫变化的临床意义尚不清楚。在此，我们评估了T细胞转录信使核糖核酸谱和免疫表型，以将免疫衰老、耗竭和无反应性与接受ASCT的MM患者队列中的临床终点相关联。ASCT诱导了T细胞的整体转录变化，并改变了T细胞亚型、T细胞活化和耗竭标志物的分子水平。这些变化包括CD4/CD8比值降低、向Th1亚群倾斜、共刺激受体CD27和CD28表达降低、T细胞活化增强以及免疫调节分子LAG3和PD1表达增加。多色流式细胞术实验证实循环CD4和CD8亚群发生改变，并向分化的效应细胞倾斜。此外，ASCT促进了CD3CD4亚群中的耗竭免疫表型和CD3CD8亚群中的衰老免疫表型。具有免疫调节功能的表面分子也出现了亚群特异性的表达改变。ASCT通过增加血浆HVEM和TIM3来影响具有免疫调节功能的分子的可溶性水平。高分子LAG3水平与ASCT后无事件生存期较差相关（风险比=5.44；置信区间，1.92至15.46；P = 0.001；校正P[控制错误发现率]=0.038）。通过在分子和表型水平上对PBTL进行全面评估，我们发现ASCT诱导了T细胞的整体改变以及CD4和CD8亚群特异性变化。此外，LAG3成为ASCT后不良事件的早期生物标志物。这些发现将支持针对MM免疫缺陷的治疗策略的开发，以增强或恢复T细胞反应。
