Wang Ling, Cao Na-Na, Wang Shan, Man Hong-Wei, Li Peng-Fei, Shan Bao-En
Cancer Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.
Blood Transfusion Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.
Tumour Biol. 2016 Mar;37(3):2961-71. doi: 10.1007/s13277-015-4132-5. Epub 2015 Sep 28.
The coinhibitory molecules, B7-H3 and B7-H4, have shown negative regulation in T cell activation and tumor-associated macrophage (TAM) polarization in tumor-specific immunity. Here, we investigated the expression of B7-H3 and B7-H4 in human and murine esophageal squamous cell carcinoma (ESCC) tissues to define their clinical significance and mechanism in a tumor microenvironment. In the present study, B7-H3 and B7-H4 were expressed in 90.6 and 92.7 % samples, respectively. High B7-H3 and B7-H4 expression was associated with advanced TNM stage and lymph node metastasis (p < 0.05, respectively). Patients with both B7-H3 and B7-H4 high-expressed tumors had the poorest prognosis (26.7 months), whereas those with both low-expressed tumors had the best survival (56.7 months). B7-H3 and B7-H4 expression were inclined to be positively related to the infiltration intensity of Treg cells and TAMs (p < 0.05, respectively), and B7-H3 expression is negatively associated with the intensity of CD8(+) T cells (p < 0.05). In 4-nitroquinoline 1-oxide (4-NQO)-induced murine models, high B7-H3 expression could only be detected at carcinoma stage, but abnormal B7-H4 expression appeared a little earlier at dysplasia stage. In vitro studies revealed that knockdown of B7-H3 on tumor cells suppressed ESCC cell migration and invasion, while knockdown of B7-H4 could inhibit ESCC cell growth. Overall, B7-H3 and B7-H4 are involved in ESCC progression and development and their coexpression could be valuable prognostic indicators. Interference of these negative regulatory molecules might be a new strategy for treating ESCC.
共抑制分子B7-H3和B7-H4在肿瘤特异性免疫中对T细胞活化和肿瘤相关巨噬细胞（TAM）极化表现出负向调节作用。在此，我们研究了B7-H3和B7-H4在人及小鼠食管鳞状细胞癌（ESCC）组织中的表达情况，以明确它们在肿瘤微环境中的临床意义及机制。在本研究中，B7-H3和B7-H4分别在90.6%和92.7%的样本中表达。B7-H3和B7-H4的高表达与晚期TNM分期及淋巴结转移相关（分别为p<0.05）。B7-H3和B7-H4均高表达肿瘤的患者预后最差（26.7个月），而两者均低表达肿瘤的患者生存期最长（56.7个月）。B7-H3和B7-H4的表达倾向于与Treg细胞和TAM的浸润强度呈正相关（分别为p<0.05），且B7-H3的表达与CD8(+)T细胞的强度呈负相关（p<0.05）。在4-硝基喹啉1-氧化物（4-NQO）诱导的小鼠模型中，仅在癌阶段可检测到B7-H3的高表达，但在发育异常阶段B7-H4的异常表达出现得稍早。体外研究表明，敲低肿瘤细胞上的B7-H3可抑制ESCC细胞的迁移和侵袭，而敲低B7-H4可抑制ESCC细胞生长。总体而言，B7-H3和B7-H4参与了ESCC的进展和发展，它们的共表达可能是有价值的预后指标。干扰这些负调节分子可能是治疗ESCC的一种新策略。
