Zhang Yong, Cui Kaisa, Yang Yaoxiang, Liu Bingxin, Zhu Minzheng, Chen Hanqing, Zhao Chong, Zhou Youlian, Nie Yuqiang
Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, People's Republic of China.
Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, People's Republic of China.
J Hepatocell Carcinoma. 2023 Jul 8;10:1051-1067. doi: 10.2147/JHC.S410756. eCollection 2023.
Immune checkpoint (IC) inhibitor-related immunotherapies have attracted considerable attention in hepatocellular carcinoma (HCC). High IC expression and high tumor infiltrating lymphocyte levels are the current indicators of sensitivity to IC inhibitors. Thus, it is imperative to apply precision medicine strategies for patient selection.
Six independent HCC cohorts were used for analysis at the single-cell and tissue levels. Multiplex immunofluorescence and immunochemistry staining assays were used to validate our results. A series of methodologies were used for immune-related evaluations.
Herein, we uncovered a unique CD8CD274 cell subpopulation that is associated with tumor progression and poor survival in HCC at the single-cell level. We assessed this subset at the tissue level and found that the prognostic significance of CD274 is dependent on CD8A expression in HCC. Subsequently, we identified a unique high-risk subpopulation that showed high CD8A expression coupled with intense CD274 expression in multiple HCC cohorts. CD8ACD274 subgroup was correlated with malignant indexes and remained an independent prognostic factor when considering the influence of these indexes. Molecular characteristic analyses showed that the CD8ACD274 subgroup harbored more mutations, had higher immune response activity and presented enrichment of cancer-related biological processes. Moreover, this high-risk subpopulation in HCC was characterized by high immune cell infiltration, low tumor purity, and enrichment of cancer-related signatures. Finally, cases with this phenotype demonstrated higher immunomodulator and IC levels and greater sensitivity to IC inhibitors.
Our findings illustrate that some HCC patients may have a poor prognosis despite high CD8 T-cell infiltration. These patients would probably benefit from IC inhibitor-based combination treatment.
免疫检查点（IC）抑制剂相关的免疫疗法在肝细胞癌（HCC）中引起了广泛关注。高IC表达和高肿瘤浸润淋巴细胞水平是目前对IC抑制剂敏感性的指标。因此，应用精准医学策略进行患者选择势在必行。
六个独立的HCC队列用于单细胞和组织水平的分析。采用多重免疫荧光和免疫化学染色分析来验证我们的结果。一系列方法用于免疫相关评估。
在此，我们在单细胞水平上发现了一个独特的CD8⁺CD274⁺细胞亚群，其与HCC的肿瘤进展和不良生存相关。我们在组织水平上评估了这个亚群，发现CD274的预后意义取决于HCC中CD8A的表达。随后，我们在多个HCC队列中确定了一个独特的高危亚群，其显示出高CD8A表达以及强烈的CD274表达。CD8A⁺CD274⁺亚组与恶性指标相关，并且在考虑这些指标的影响时仍然是一个独立的预后因素。分子特征分析表明，CD8A⁺CD274⁺亚组具有更多的突变，具有更高的免疫反应活性，并呈现出癌症相关生物学过程的富集。此外，HCC中的这个高危亚群的特征是高免疫细胞浸润、低肿瘤纯度以及癌症相关特征的富集。最后，具有这种表型的病例表现出更高的免疫调节剂和IC水平，并且对IC抑制剂更敏感。
我们的研究结果表明，一些HCC患者尽管有高CD8 T细胞浸润，但预后可能较差。这些患者可能会从基于IC抑制剂的联合治疗中受益。
