Interleukin‐17‐educated monocytes suppress cytotoxic T‐cell function through B7‐H1 in hepatocellular carcinoma patients
Interleukin‐17‐educated monocytes suppress cytotoxic T‐cell function through B7‐H1 in hepatocellular carcinoma patients
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DOI：
10.1002/eji.201041282
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发表时间：
2011-08
影响因子：
5.4
通讯作者：
Qiyi Zhao;Xiao Xiao-Xiao;Yan Wu;Yi Wei;Ling Zhu;Jia Zhou;D. Kuang
中科院分区：
文献类型：
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作者：
Qiyi Zhao;Xiao Xiao-Xiao;Yan Wu;Yi Wei;Ling Zhu;Jia Zhou;D. Kuang
大量证据表明，炎症是肿瘤进展的关键组成部分。最近在肿瘤中发现了促炎IL - 17产生细胞，但IL - 17对肿瘤中抗原呈递细胞的影响目前尚不清楚。我们最近发现B7‐H1+巨噬细胞（Mφs）主要富集在肝细胞癌（hcc）的瘤周基质中。在这里，我们发现在同一区域产生IL - 17的细胞和表达m - φs的B7 - H1之间存在正相关。来自HCC组织的B7‐H1+单核细胞/ m - φs比B7‐H1 -细胞表达更多的HLA‐DR、CD80和CD86。因此，IL - 17能够以剂量依赖性的方式激活单核细胞表达B7 - H1。虽然从肝癌细胞中提取的培养上清液也能诱导单核细胞表达B7‐H1，但IL‐17还能增加肝癌介导的B7‐H1表达。IL - 17活化单核细胞释放的自分泌炎性细胞因子刺激了B7 - H1的表达。此外，这些暴露于IL - 17的单核细胞在体外有效地抑制了细胞毒性T细胞免疫；通过阻断B7‐H1对这些单核细胞的作用，这种效果可以逆转。与此一致，来自HCC组织的细胞毒性T细胞表达显著的B7‐H1受体程序性死亡1 (PD‐1)，并表现出衰竭表型。这些数据揭示了不同基质细胞之间的协同作用，以对抗肿瘤中的T细胞反应。这种IL - 17介导的免疫耐受应该考虑到合理设计有效的基于免疫的抗癌疗法。
Substantial evidence indicates that inflammation is a critical component of tumor progression. The proinflammatory IL‐17‐producing cells have recently been detected in tumors, but the effect of IL‐17 on antigen‐presenting cells in tumors is presently unknown. We recently found that B7‐H1+ macrophages (Mφs) were enriched predominantly in the peritumoral stroma of hepatocellular carcinomas (HCCs). Here, we found a positive correlation between IL‐17‐producing cells and B7‐H1‐expressing Mφs in the same area. The B7‐H1+ monocytes/Mφs from HCC tissues expressed significantly more HLA‐DR, CD80, and CD86 than B7‐H1– cells. Accordingly, IL‐17 could activate monocytes to express B7‐H1 in a dose‐dependent manner. Although culture supernatants derived from hepatoma cells also induced B7‐H1 expression on monocytes, IL‐17 additionally increased hepatoma‐mediated B7‐H1 expression. Autocrine inflammatory cytokines released from IL‐17‐activated monocytes stimulated B7‐H1 expression. Moreover, these IL‐17‐exposed monocytes effectively suppressed cytotoxic T‐cell immunity in vitro; the effect could be reversed by blocking B7‐H1 on those monocytes. Consistent with this, cytotoxic T cells from HCC tissues expressed significant B7‐H1 receptor programmed death 1 (PD‐1) and exhibited an exhausted phenotype. These data reveal a fine‐tuned collaborative action between different stromal cells to counteract T‐cell responses in tumors. Such IL‐17‐mediated immune tolerance should be considered for the rational design of effective immune‐based anti‐cancer therapies.