Elashi Asma A, Sasidharan Nair Varun, Taha Rowaida Z, Shaath Hibah, Elkord Eyad
Cancer Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
Institute of Cancer Sciences, University of Manchester, Manchester, UK.
Oncoimmunology. 2018 Nov 10;8(2):e1542918. doi: 10.1080/2162402X.2018.1542918. eCollection 2019.
Aberrant expression of immune checkpoints (ICs) in cancer creates an immunosuppressive microenvironment, which supports immune evasion of tumor cells. We have recently reported that epigenetic modifications are critical for ICs expression in the tumor microenvironment (TME) of primary breast cancer (PBC) and colorectal cancer (CRC). Herein, we investigated transcriptomic expression of ICs (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT) and PD-L1 in peripheral blood of PBC and CRC patients, compared to healthy donors (HD). We found that expressions of TIM-3, TIGIT, PD-L1 were significantly upregulated, while LAG-3 expression was downregulated in peripheral blood of PBC and CRC patients. Demethylation enzymes TET2 and TET3 were also upregulated. In addition, promoter DNA methylation status of PD-1 was significantly hypermethylated, while PD-L1 was hypomethylated in PBC and CRC patients. Furthermore, TIGIT was significantly hypomethylated only in CRC patients. Remarkably, promoter methylation status of LAG-3, TIGIT and PD-L1 was in concordance with transcriptomic expression in CRC: the more the hypomethylation, the higher the expression. In comparison, we found that CTLA-4, TIM-3, TIGIT and PD-L1 in PBC, and CTLA-4 in CRC patients were significantly upregulated in peripheral blood, compared with tumor tissues of the same patients. However, demethylation status of all ICs was higher in TT, except for TIGIT in PBC, and CTLA-4 in CRC patients. These data indicate that the underlying mechanisms behind peripheral upregulation of PD-L1 and TIGIT in cancer patients could be due to aberrant promoter methylation profile. Moreover, demethylation inhibitors together with anti-PD-L1/anti-TIGIT could be a more efficient therapeutic strategy in cancer patients.
癌症中免疫检查点（ICs）的异常表达会产生免疫抑制微环境，这有助于肿瘤细胞逃避免疫监视。我们最近报道，表观遗传修饰对于原发性乳腺癌（PBC）和结直肠癌（CRC）肿瘤微环境（TME）中ICs的表达至关重要。在此，我们研究了PBC和CRC患者外周血中ICs（PD-1、CTLA-4、LAG-3、TIM-3、TIGIT）和PD-L1的转录组表达，并与健康供体（HD）进行了比较。我们发现，PBC和CRC患者外周血中TIM-3、TIGIT、PD-L1的表达显著上调，而LAG-3表达下调。去甲基化酶TET2和TET3也上调。此外，PBC和CRC患者中PD-1的启动子DNA甲基化状态显著高甲基化，而PD-L1则低甲基化。此外，仅在CRC患者中TIGIT显著低甲基化。值得注意的是，LAG-3、TIGIT和PD-L1的启动子甲基化状态与CRC中的转录组表达一致：甲基化程度越低，表达越高。相比之下，我们发现与同一患者的肿瘤组织相比，PBC患者外周血中的CTLA-4、TIM-3、TIGIT和PD-L1以及CRC患者外周血中的CTLA-4显著上调。然而，除了PBC中的TIGIT和CRC患者中的CTLA-4外，所有ICs在肿瘤组织中的去甲基化状态更高。这些数据表明，癌症患者外周血中PD-L1和TIGIT上调的潜在机制可能是由于异常的启动子甲基化谱。此外，去甲基化抑制剂与抗PD-L1/抗TIGIT联合使用可能是癌症患者更有效的治疗策略。
