Table_2_Aging-related features predict prognosis and immunotherapy efficacy in hepatocellular carcinoma.xls

The aging microenvironment serves important roles in cancers. However, most studies focus on circumscribed hot spots such as immunity and metabolism. Thus, it is well ignored that the aging microenvironment contributes to the proliferation of tumor. Herein, we established three prognosis-distinctive aging microenvironment subtypes, including AME1, AME2, and AME3, based on aging-related genes and characterized them with “Immune Exclusion,” “Immune Infiltration,” and “Immune Intermediate” features separately. AME2-subtype tumors were characterized by specific activation of immune cells and were most likely to be sensitive to immunotherapy. AME1-subtype tumors were characterized by inhibition of immune cells with high proportion of Catenin Beta 1 (CTNNB1) mutation, which was more likely to be insensitive to immunotherapy. Furthermore, we found that CTNNB1 may inhibit the expression of C-C Motif Chemokine Ligand 19 (CCL19), thus restraining immune cells and attenuating the sensitivity to immunotherapy. Finally, we also established a robust aging prognostic model to predict the prognosis of patients with hepatocellular carcinoma. Overall, this research promotes a comprehensive understanding about the aging microenvironment and immunity in hepatocellular carcinoma and may provide potential therapeutic targets for immunotherapy.

衰老微环境在癌症进程中发挥重要作用。然而，多数现有研究仅聚焦于免疫、代谢等有限的研究热点领域，因此衰老微环境促进肿瘤增殖这一关键现象长期被忽视。本研究基于衰老相关基因，构建了三种具有预后差异的衰老微环境亚型（AME1、AME2及AME3），并分别将其表征为“免疫排斥型（Immune Exclusion）”、“免疫浸润型（Immune Infiltration）”与“免疫中间型（Immune Intermediate）”。其中，AME2亚型肿瘤以免疫细胞特异性激活为特征，最有可能对免疫治疗敏感；AME1亚型肿瘤则表现为免疫细胞受抑，且携带高比例的β-连环蛋白1（Catenin Beta 1, CTNNB1）突变，这类肿瘤对免疫治疗多不敏感。进一步研究发现，CTNNB1可抑制C-C基序趋化因子配体19（C-C Motif Chemokine Ligand 19, CCL19）的表达，进而抑制免疫细胞活性并削弱免疫治疗敏感性。最后，本研究还构建了一个稳健的衰老预后模型，用于预测肝细胞癌（hepatocellular carcinoma）患者的预后情况。综上，本研究推动了学界对肝细胞癌中衰老微环境与免疫机制的全面认知，可为免疫治疗提供潜在治疗靶点。