Mukai Shohei, Kanzaki Hiroaki, Ogasawara Sadahisa, Ishino Takamasa, Ogawa Keita, Nakagawa Miyuki, Fujiwara Kisako, Unozawa Hidemi, Iwanaga Terunao, Sakuma Takafumi, Fujita Naoto, Koroki Keisuke, Kobayashi Kazufumi, Kanogawa Naoya, Kiyono Soichiro, Nakamura Masato, Kondo Takayuki, Saito Tomoko, Nakagawa Ryo, Suzuki Eiichiro, Ooka Yoshihiko, Muroyama Ryosuke, Nakamoto Shingo, Tawada Akinobu, Chiba Tetsuhiro, Arai Makoto, Kato Jun, Shiina Manayu, Ota Masayuki, Ikeda Jun-Ichiro, Takiguchi Yuichi, Ohtsuka Masayuki, Kato Naoya
Department of Gastroenterology, Graduate School of Medicine Chiba University Chiba Japan.
Translational Research and Development Center Chiba University Hospital Chiba Japan.
JGH Open. 2021 Oct 1;5(11):1266-1274. doi: 10.1002/jgh3.12660. eCollection 2021 Nov.
Immune checkpoint inhibitors and their combination with other agents have recently been available in advanced hepatocellular carcinoma (HCC). Hence, a thorough understanding of the tumor microenvironment based on tumor samples is yet to be achieved. This study aimed to explore the tumor microenvironment in advanced HCC in terms of microsatellite instability-high (MSI-H) by using tumor samples from advanced HCC patients eligible for systemic therapy.
MSI-H was assessed by polymerase chain reaction, and the expression of mismatch repair proteins, PD-L1, CD8, VEGF, and HLA-class1 was evaluated by immunohistochemistry. Whole-exome sequencing was performed for MSI-H tumor samples.
Of 50 patients, one (2.0%) was confirmed with MSI-H. In the MSI-H advanced HCC tumor, a high tumor mutation burden, infiltration of CD8 lymphocytes, and low expression of VEGF were identified. Although PD-L1 expression was negative, there was shrinkage of tumor following pembrolizumab. However, another tumor nonresponsive to pembrolizumab was present simultaneously. Checking the Cancer Genome Atlas (TCGA) database, we found a similar case to this patient. The TCGA case had unique gene features of miR-21 and miR-155 overexpression and hypermethylation of the gene.
We identified a very small number of MSI-H cases in HCC using one tumor biopsy sample for each patient with advanced HCC. In addition, epigenetic aberrations possibly lead to MSI-H in HCC patients. Since different HCC clones might coexist in the liver, sampling from multiple tumors should be considered to clarify the true proportion of MSI-H in HCC and to analyze tumor microenvironments.
免疫检查点抑制剂及其与其他药物的联合应用最近已在晚期肝细胞癌（HCC）中可用。因此，基于肿瘤样本对肿瘤微环境的全面了解尚未实现。本研究旨在通过使用符合全身治疗条件的晚期HCC患者的肿瘤样本，从微卫星高度不稳定（MSI-H）方面探索晚期HCC的肿瘤微环境。
通过聚合酶链反应评估MSI-H，并通过免疫组织化学评估错配修复蛋白、PD-L1、CD8、VEGF和HLA-1类的表达。对MSI-H肿瘤样本进行全外显子测序。
在50例患者中，1例（2.0%）被确认为MSI-H。在MSI-H晚期HCC肿瘤中，发现肿瘤突变负荷高、CD8淋巴细胞浸润和VEGF低表达。尽管PD-L1表达为阴性，但帕博利珠单抗治疗后肿瘤出现缩小。然而，同时存在另一例对帕博利珠单抗无反应的肿瘤。检查癌症基因组图谱（TCGA）数据库时，我们发现了与该患者相似的病例。TCGA病例具有miR-21和miR-155过表达以及该基因高甲基化的独特基因特征。
我们在晚期HCC患者中使用每个患者的一份肿瘤活检样本，在HCC中鉴定出极少数MSI-H病例。此外，表观遗传异常可能导致HCC患者出现MSI-H。由于不同的HCC克隆可能在肝脏中共存，应考虑从多个肿瘤进行采样，以阐明HCC中MSI-H的真实比例并分析肿瘤微环境。
