低分化肝细胞癌的免疫微环境及其对PD⁃1抑制剂疗效的评估价值

Immune microenvironment of poorly differentiated hepatocellular carcinoma and its value in assessing the efficacy of PD⁃1 inhibitors

目的探索不同分化程度肝细胞癌(hepatocellular carcinoma,HCC)的预后差别,以及免疫治疗对低分化HCC的疗效。方法通过收集SEER数据库及于西安交通大学第一附属医院接受手术切除的HCC患者的资料进行临床数据分析,使用TCGA⁃LIHC seq数据分析低分化HCC的免疫微环境特征,结合1例低分化HCC患者探索接受免疫治疗的效果。结果共收集SEER数据库4114例及西安交通大学第一附属医院590例HCC患者数据,生存分析显示,低分化HCC患者均较高⁃中分化患者的总生存期短(P<0.001)。WGCNA及通路富集分析显示,影响HCC分化及预后的基因通路主要富集在E2F1相关通路,该通路同时也会影响肿瘤组织免疫细胞浸润。TCGA⁃LIHC seq数据分析证实低分化HCC中CD8+T淋巴细胞富集并存在PD⁃1高表达。临床数据分析显示,1例低分化HCC患者接受免疫治疗后达到临床完全缓解,提示低分化HCC可能是免疫治疗的潜在受益人群。结论低分化HCC预后差,基于低分化HCC的PD⁃1+CD8+T细胞高度浸润的免疫微环境特征,其接受免疫治疗可能获得较好疗效。

Objective To analyze the prognostic differences of hepatocellular carcinoma(HCC)with different levels of differentiation and to assess the efficacy of immunotherapy on poorly differentiated HCC.Methods The data of SEER database and HCC patients who underwent surgical resection at the First Affiliated Hospital of Xi′an Jiaotong University were collected for the clinical data analysis.The immune microenvironment characteristics of poorly differentiated HCC were analyzed by TCGA⁃LIHC seq data,and the efficacy of immu⁃notherapy was analyzed in combination with one patients with poorly differentiated HCC.Results The data of 4,114 patients from SEER database and 590 patients from the First Affiliated Hospital of Xi′an Jiaotong University were collected,and the survival analysis showed that the overall survival of patients with poorly differentiated HCC was worse than that of patients with high⁃moderately differentiated HCC(P<0.001).WGCNA and pathway enrichment analysis showed that the gene pathways affecting HCC differentiation and prognosis were mainly enriched in the E2F1⁃related pathway,which also affected immune cell infiltration in tumor tissues.TCGA⁃LIHC seq data analysis confirmed the enrichment of CD8+T lymphocytes and high PD⁃1 expression in poorly differentiated HCC.Clinical data analysis showed that one patient with poorly differentiated HCC achieved complete response status after receiving immunotherapy,suggesting that poorly differentiated HCC was a potential beneficiary for immunotherapy.Conclusions The poorly differentiated HCC has a poor prognosis.The characteristics of the immune microenvironment with highly infiltrated PD⁃1+CD8+T cells of poorly differentiated HCC implies that immunotherapy may achieve better outcome.