The AP1-dependent secretion of galectin-1 by Reed - Sternberg cells fosters immune privilege in classical Hodgkin lymphoma
The AP1-dependent secretion of galectin-1 by Reed - Sternberg cells fosters immune privilege in classical Hodgkin lymphoma
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DOI：
10.1073/pnas.0706017104
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发表时间：
2007-08-07
影响因子：
11.1
通讯作者：
Shipp, Margaret A.
中科院分区：
文献类型：
--
作者：
Juszczynski, Przemyslaw;Ouyang, Jing;Shipp, Margaret A.
经典霍奇金淋巴瘤（cHL）在广泛的炎性浸润物中含有少量的肿瘤性Reed-Sternberg（RS）细胞，所述炎性浸润物包括丰富的T辅助（Th）-2和T调节（T-reg）细胞。T细胞浸润的偏斜性质和缺乏有效的宿主抗肿瘤免疫应答表明RS细胞使用有效的机制来逃避免疫攻击。在cHL中筛选T细胞抑制分子时，我们发现RS细胞通过AP 1依赖性增强子选择性过表达免疫调节聚糖结合蛋白半乳糖凝集素-I（Gall）。在活化的T细胞和霍奇金细胞系的共培养物中，RNAi介导的RS细胞Gall的阻断增加了T细胞活力并恢复了Thl/Th 2平衡。相反，Gall处理活化的T细胞有利于Th 2细胞因子的分泌和CD 4（+）CD 25（高）FOXP 3（+）T-reg细胞的扩增。这些数据直接暗示RS细胞Gall在cHL中免疫抑制性Th 2/T-reg偏斜微环境的发展和维持中，并为RS细胞中Gall的选择性表达提供了分子基础。因此，Gall代表了恢复cHL免疫监视的潜在治疗靶点。
Classical Hodgkin lymphomas (cHLs) contain small numbers of neoplastic Reed-Sternberg (RS) cells within an extensive inflammatory infiltrate that includes abundant T helper (Th)-2 and T regulatory (T-reg) cells. The skewed nature of the T cell infiltrate and the lack of an effective host antitumor immune response suggest that RS cells use potent mechanisms to evade immune attack. In a screen for T cell-inhibitory molecules in cHL, we found that RS cells selectively overexpressed the immunoregulatory glycan-binding protein, galectin-l (Gall), through an AP1-dependent enhancer. In cocultures of activated T cells and Hodgkin cell lines, RNAi-mediated blockade of RS cell Gall increased T cell viability and restored the Thl/Th2 balance. In contrast, Gall treatment of activated T cells favored the secretion of Th2 cytokines and the expansion of CD4(+)CD25(high) FOXP3(+) T-reg cells. These data directly implicate RS cell Gall in the development and maintenance of an immunosuppressive Th2/T-reg-skewed microenvironment in cHL and provide the molecular basis for selective Gall expression in RS cells. Thus, Gall represents a potential therapeutic target for restoring immune surveillance in cHL.