Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell-rich and exhausted T-effector microenvironment
Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell-rich and exhausted T-effector microenvironment
复制标题
DOI：
10.1182/blood-2018-04-843714
复制
发表时间：
2018-08-23
期刊：
影响因子：
20.3
通讯作者：
Shipp, Margaret A.
中科院分区：
文献类型：
--
作者：
Cader, Fathima Zumla;Schackmann, Ron C. J.;Shipp, Margaret A.
在经典霍奇金淋巴瘤（cHL）中，宿主抗肿瘤免疫反应无效。 Hodgkin Reed-Sternberg (HRS) 细胞具有逃避免疫系统的多方面机制，包括 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) 基因改变、PD-1 配体的过度表达以及相关的 T 细胞耗竭和异常抗原呈递的其他结构基础。 PD-1 阻断在 cHL 中的临床成功表明肿瘤微环境 (TME) 包含可逆耗竭的 T 效应细胞 (Teffs)。然而，在 HRS 细胞上 b2-微球蛋白/主要组织相容性复合体 (MHC) I 类缺失的患者中观察到持久的反应，这提高了非 CD81 T 细胞介导的 PD-1 阻断功效机制的可能性。这些观察结果凸显了对 cHL TME 进行详细分析的必要性。使用定制的飞行时间质谱流式细胞术面板，我们同时评估了诊断性 cHL 活检和对照反应性淋巴结/扁桃体 (RLNT) 样本的细胞悬液。免疫细胞亚群的精确表型分析揭示了 cHL 和 RLNT 之间的显着差异。 cHL 中的 TME 富含 CD41 T 细胞，HRS 细胞上 MHC I 类表达经常缺失。在 cHL 中，我们发现辅助性 T 细胞 1 (Th1) 极化的 Teff 和调节性 T 细胞 (Treg) 同时扩增。 cHL Th1 Tregs 表达很少或不表达 PD-1，而 Th1 Teff 则表达 PD-11。 PD-1 表达差异以及可能的功能性 Th1 极化 CD41 Tregs 和耗尽的 Teff 可能代表 cHL 中免疫抑制的互补机制。
In classical Hodgkin lymphoma (cHL), the host antitumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system, including 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) genetic alterations, overexpression of PD-1 ligands, and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exhausted T effector cells (Teffs). However, durable responses are observed in patients with b2-microglobulin/major histocompatibility complex (MHC) class I loss on HRS cells, raising the possibility of non-CD81 T cell-mediated mechanisms of efficacy of PD-1 blockade. These observations highlight the need for a detailed analysis of the cHL TME. Using a customized time-of-flight mass cytometry panel, we simultaneously assessed cell suspensions from diagnostic cHL biopsies and control reactive lymph node/tonsil (RLNT) samples. Precise phenotyping of immune cell subsets revealed salient differences between cHLs and RLNTs. The TME in cHL is CD41 T-cell rich, with frequent loss of MHC class I expression on HRS cells. In cHLs, we found concomitant expansion of T helper 1 (Th1)-polarized Teffs and regulatory T cells (Tregs). The cHL Th1 Tregs expressed little or no PD-1, whereas the Th1 Teffs were PD-11. The differential PD-1 expression and likely functional Th1-polarized CD41 Tregs and exhausted Teffs may represent complementary mechanisms of immunosuppression in cHL.