Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
The First Affiliated Hospital of Zhengzhou University, Henan Research Centre for Organ Transplantation, Zhengzhou, China.
Front Immunol. 2022 Jul 27;13:970117. doi: 10.3389/fimmu.2022.970117. eCollection 2022.
Necroptosis is a novel pattern of immunogenic cell death and has triggered an emerging wave in antitumor therapy. More evidence has suggested the potential associations between necroptosis and intra-tumoral heterogeneity. Currently, the underlying role of necroptosis remains elusive in hepatocellular carcinoma (HCC) at antitumor immunity and inter-tumoral heterogeneity.
This study enrolled a total of 728 HCC patients and 139 immunotherapy patients from eight public datasets. The consensus clustering approach was employed to depict tumor heterogeneity of cancer necroptosis. Subsequently, our study further decoded the heterogeneous clinical outcomes, genomic landscape, biological behaviors, and immune characteristics in necroptosis subtypes. For each patient, providing curative clinical recommendations and developing potential therapeutic drugs were used to promote precise medicine.
With the use of the weighted gene coexpression network analysis (WGCNA) algorithm, necroptosis-associated long non-coding RNAs (lncRNAs) (NALRs) were identified in HCC. Based on the NALR expression, two heterogeneous subtypes were decoded with distinct clinical outcomes. Compared to patients in C1, patients in C2 harbored superior pathological stage and presented more unfavorable overall survival and recurrence-free survival. Then, the robustness and reproducibility of necroptosis subtypes were further validated the nearest template prediction (NTP) approach and classical immune phenotypes. Through comprehensive explorations, C1 was characterized by enriched immune-inflammatory and abundant immune infiltration, while C2 possessed elevated proliferative and metabolic activities and highly genomic instability. Moreover, our results indicated that C1 was more prone to obtain desirable benefits from immunotherapy. For patients in C2, numerous underlying therapeutic agents were developed, which might produce significant efficacy.
This study identified two necroptosis subtypes with distinct characteristics, decoding the tumor heterogeneity. For an individualized patient, our work tailored corresponding treatment strategies to improve clinical management.
坏死性凋亡是一种新型的免疫原性细胞死亡模式，在抗肿瘤治疗中引发了一股新潮流。越来越多的证据表明，坏死性凋亡与肿瘤内异质性之间存在潜在关联。目前，坏死性凋亡在抗肿瘤免疫和肿瘤间异质性中在肝细胞癌（HCC）中的潜在作用仍不明确。
本研究共纳入来自八个公共数据集的 728 名 HCC 患者和 139 名免疫治疗患者。采用共识聚类方法描绘癌症坏死性凋亡的肿瘤异质性。随后，我们的研究进一步解码了坏死性凋亡亚型中不同的临床结局、基因组景观、生物学行为和免疫特征。对于每位患者，提供有针对性的临床建议并开发潜在的治疗药物，以促进精准医学的发展。
使用加权基因共表达网络分析（WGCNA）算法，在 HCC 中鉴定出与坏死性凋亡相关的长链非编码 RNA（lncRNA）（NALR）。基于 NALR 的表达，解码出两种具有不同临床结局的异质性亚型。与 C1 患者相比，C2 患者具有更有利的病理分期，表现出更不利的总生存期和无复发生存期。然后，使用最近模板预测（NTP）方法和经典免疫表型进一步验证了坏死性凋亡亚型的稳健性和可重复性。通过全面探索，C1 表现为丰富的免疫炎症和丰富的免疫浸润，而 C2 则表现出更高的增殖和代谢活性以及高度的基因组不稳定性。此外，我们的研究结果表明，C1 更有可能从免疫治疗中获得理想的益处。对于 C2 患者，开发了许多潜在的治疗药物，可能会产生显著疗效。
本研究确定了两种具有不同特征的坏死性凋亡亚型，解码了肿瘤异质性。对于个体化患者，我们的工作定制了相应的治疗策略，以改善临床管理。
