Expression of multiple immune checkpoint molecules on T cells in malignant ascites from epithelial ovarian carcinoma
Expression of multiple immune checkpoint molecules on T cells in malignant ascites from epithelial ovarian carcinoma
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DOI：
10.3892/ol.2018.8101
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发表时间：
2018-05-01
期刊：
影响因子：
2.9
通讯作者：
Fujiwara, Keiichi
中科院分区：
文献类型：
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作者：
Imai, Yuichi;Hasegawa, Kosei;Fujiwara, Keiichi
免疫检查点分子的表达，包括程序性细胞死亡蛋白-1（PD-1），已经在各种类型的癌症中的T细胞上报道。然而，这些分子在上皮性卵巢癌（EOC）的肿瘤微环境中的表达状态尚未得到研究。本文分析了54例卵巢癌恶性腹水患者的临床资料。应用流式细胞术检测卵巢癌腹水中PD-1、LAG-3、TIM-3、B和BTLA在CD 4（+）和CD 8（+）T细胞上的表达。还分析了肿瘤细胞中PD-L1、HLA-DR阳性细胞中PD-L2和腹水中半乳糖凝集素-9的表达。此外，进行腹水的细胞因子分析以了解EOC的免疫微环境。PD-1、LAG-3、TIM-3和BTLA分别在65.8%、10.6%、4.3%和37.6%的CD4（+）T细胞上和57.7%、5.0%、4.9%和15.7%的CD8（+）T细胞上表达。程序性细胞死亡蛋白-1（PD-1）、LAG-3和BTLA在CD4（+）T细胞上的表达频率高于CD8（+）T细胞。进一步研究免疫检查点的共表达，结果显示39例（72.2%）和37例（68.5%）患者分别在CD4（+）T细胞和CD8（+）T细胞上表达多个免疫检查点。此外，腹水中较低水平的TNF-α和白细胞介素-6与CD8（+）T细胞上的多个免疫检查点表达显著相关。目前的研究结果表明，多种免疫检查点分子在EOC肿瘤微环境中的T细胞上表达，并且结果可能表明同时阻断免疫检查点以控制EOC的意义。
Expression of immune checkpoint molecules, including programmed cell death protein-1 (PD-1), has been reported on T cells in various types of cancer. However, the expression status of these molecules in the tumor microenvironment of epithelial ovarian cancer (EOC) has not yet been studied. A total of 54 cases of malignant ascites from patients with EOC were analyzed in the present study. The expression of PD-1, lymphocyte-activation gene-3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and B and T lymphocyte attenuator (BTLA) on cluster of differentiation (CD)4(+) and CD8(+) T cells in malignant EOC ascites were investigated using multicolor flow cytometric analysis. The expression of PD-L1 in tumor cells, PD-L2 in HLA-DR-positive cells and galectin-9 in ascitic fluid was also analyzed. In addition, cytokine profiling of ascitic fluid was performed to understand the immune microenvironment of EOC. PD-1, LAG-3 TIM-3, and BTLA were expressed on 65.8, 10.6, 4.3 and 37.6% of CD4(+) T cells, and on 57.7, 5.0, 4.9 and 15.7% of CD8(+) T cells, respectively. Programmed cell death protein-1 (PD-1), LAG-3 and BTLA were more frequently expressed on CD4(+) compared with CD8(+) T cells. The co-expression of immune checkpoints was further investigated and results indicated that 39 (72.2%) and 37 patients (68.5%) expressed multiple immune checkpoints on CD4(+) T cells and CD8(+) T cells, respectively. In addition, lower levels of TNF-alpha and interleukin-6 in ascitic fluid were significantly associated with multiple immune checkpoint expression on CD8(+) T cells. The present findings indicated that multiple immune checkpoint molecules were expressed on T cells in the EOC tumor microenvironment and the results may suggest the significance of simultaneous blockade of immune checkpoints to control EOC.