Shen Qianyun, He Yin, Qian Jiajie, Wang Xiaosheng
Department of Gastrointestinal Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Front Mol Biosci. 2022 Oct 20;9:960457. doi: 10.3389/fmolb.2022.960457. eCollection 2022.
Although current immunotherapies have achieved some successes for hepatocellular carcinoma (HCC) patients, their benefits are limited for most HCC patients. Therefore, the identification of biomarkers for promoting immunotherapeutic responses in HCC is urgently needed. Using the TCGA HCC cohort, we investigated correlations of various molecular features with antitumor immune signatures (CD8 T cell infiltration and cytolytic activity) and an immunosuppressive signature (PD-L1 expression) in HCC. These molecular features included mRNAs, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), proteins, and pathways. We found that the mutations of several oncogenes and tumor suppressor genes significantly correlated with reduced antitumor immune signatures, including , , , , and . It indicates that these genes' mutations may inhibit antitumor immune responses in HCC. Four proteins (Syk, Lck, STAT5, and Caspase-7) had significant positive expression correlations with CD8 T cell enrichment, cytolytic activity, and PD-L1 expression in HCC. It suggests that these proteins' expression could be useful biomarkers for the response to immune checkpoint inhibitors Similiarly, we identified other types of biomarkers potentially useful for predicting the response to ICIs, including miRNAs (hsa-miR-511-5p, 150-3p, 342-3p, 181a-3p, 625-5p, 4772-3p, 155-3p, 142-5p, 142-3p, 155-5p, 625-3p, 1976, 7702), many lncRNAs, and pathways (apoptosis, cytokine-cytokine receptor interaction, Jak-STAT signaling, MAPK signaling, PI3K-AKT signaling, HIF-1 signaling, ECM receptor interaction, focal adhesion, and estrogen signaling). Further, tumor mutation burden showed no significant correlation with antitumor immunity, while tumor aneuploidy levels showed a significant negative correlation with antitumor immunity. The molecular features significantly associated with HCC immunity could be predictive biomarkers for immunotherapeutic responses in HCC patients. They could also be potential intervention targets for boosting antitumor immunity and immunotherapeutic responses in HCC.
尽管目前的免疫疗法已在肝细胞癌（HCC）患者中取得了一些成功，但对大多数HCC患者来说，其益处有限。因此，迫切需要鉴定促进HCC免疫治疗反应的生物标志物。利用TCGA HCC队列，我们研究了HCC中各种分子特征与抗肿瘤免疫特征（CD8 T细胞浸润和细胞溶解活性）以及免疫抑制特征（PD-L1表达）之间的相关性。这些分子特征包括mRNA、微小RNA（miRNA）、长链非编码RNA（lncRNA）、蛋白质和信号通路。我们发现，几种癌基因和肿瘤抑制基因的突变与抗肿瘤免疫特征的降低显著相关，包括 、 、 、 和 。这表明这些基因的突变可能会抑制HCC中的抗肿瘤免疫反应。四种蛋白质（Syk、Lck、STAT5和Caspase-7）在HCC中与CD8 T细胞富集、细胞溶解活性和PD-L1表达呈显著正相关。这表明这些蛋白质的表达可能是免疫检查点抑制剂反应的有用生物标志物。同样，我们鉴定出了其他可能有助于预测对免疫检查点抑制剂（ICI）反应的生物标志物类型，包括miRNA（hsa-miR-511-5p、150-3p、342-3p、181a-3p、625-5p、4772-3p、155-3p、142-5p、142-3p、155-5p、625-3p、1976、7702）、许多lncRNA和信号通路（凋亡、细胞因子-细胞因子受体相互作用、Jak-STAT信号传导、MAPK信号传导、PI3K-AKT信号传导、HIF-1信号传导、ECM受体相互作用、粘着斑和雌激素信号传导）。此外，肿瘤突变负担与抗肿瘤免疫无显著相关性，而肿瘤非整倍体水平与抗肿瘤免疫呈显著负相关。与HCC免疫显著相关的分子特征可能是HCC患者免疫治疗反应的预测生物标志物。它们也可能是增强HCC抗肿瘤免疫和免疫治疗反应的潜在干预靶点。
