Mass cytometry dissects T cell heterogeneity in the immune tumor microenvironment of common dysproteinemias at diagnosis and after first line therapies
Mass cytometry dissects T cell heterogeneity in the immune tumor microenvironment of common dysproteinemias at diagnosis and after first line therapies
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DOI：
10.1038/s41408-019-0234-4
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发表时间：
2019-08-28
影响因子：
12.8
通讯作者：
Kumar, Shaji
中科院分区：
文献类型：
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作者：
Kourelis, Taxiarchis V.;Villasboas, Jose C.;Kumar, Shaji
随着免疫肿瘤微环境(ITME)的发展，异常蛋白血症在肿瘤细胞中通过一系列克隆性进化事件进展。新的多参数细胞术方法，如飞行时间细胞术(CyTOF)与新的门控算法相结合，可以快速表征肿瘤ITME中以前未知的表型，并更好地捕捉其异质性。在这里，我们使用了一个33个标记的细胞周期转运蛋白分析板来描述蛋白异常血症患者(MGUS、多发性骨髓瘤-MM、阴燃MM和AL淀粉样变性)在诊断和标准一线治疗(三胞胎诱导化疗和自体干细胞移植-ASCT)后的ITME。我们发现了一些新的亚群，其中一些是ITME独有的，在匹配的外周血液样本中缺失，在肿瘤免疫监视和肿瘤免疫逃逸中具有潜在的作用。我们发现AL淀粉样变性与其他髓系和“先天类”T细胞亚群浸润性较高的异常蛋白血症相比有明显的ITME。我们证明T细胞免疫衰老可能与三体患者的疾病发病机制有关。最后，我们证明了ASCT后早期与衰老和衰竭亚群的增加有关，这可能对ASCT后治疗的合理选择有一定的意义。
Dysproteinemias progress through a series of clonal evolution events in the tumor cell along with the development of a progressively more "permissive" immune tumor microenvironment (iTME). Novel multiparametric cytometry approaches, such as cytometry by time-of-flight (CyTOF) combined with novel gating algorithms can rapidly characterize previously unknown phenotypes in the iTME of tumors and better capture its heterogeneity. Here, we used a 33-marker CyTOF panel to characterize the iTME of dysproteinemia patients (MGUS, multiple myeloma-MM, smoldering MM, and AL amyloidosis) at diagnosis and after standard of care first line therapies (triplet induction chemotherapy and autologous stem cell transplant-ASCT). We identify novel subsets, some of which are unique to the iTME and absent from matched peripheral blood samples, with potential roles in tumor immunosurveillance as well as tumor immune escape. We find that AL amyloidosis has a distinct iTME compared to other dysproteinemias with higher myeloid and "innate-like" T cell subset infiltration. We show that T cell immune senescence might be implicated in disease pathogenesis in patients with trisomies. Finally, we demonstrate that the early post-ASCT period is associated with an increase of senescent and exhausted subsets, which might have implications for the rational selection of post-ASCT therapies.