免疫细胞溶解活性助力全面了解肝细胞癌的免疫格局
Immune Cytolytic Activity for Comprehensive Understanding of Immune Landscape in Hepatocellular Carcinoma.
作者信息
Takahashi Hideo, Kawaguchi Tsutomu, Yan Li, Peng Xuan, Qi Qianya, Morris Luc G T, Chan Timothy A, Tsung Allan, Otsuji Eigo, Takabe Kazuaki
机构信息
Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
出版信息
Cancers (Basel). 2020 May 13;12(5):1221. doi: 10.3390/cancers12051221.
Cytolytic activity score (CYT), defined by granzyme A and perforin expression, is a useful marker for underlying immunity. We hypothesized that CYT-high hepatocellular carcinomas (HCCs) have stronger immunogenicity and favorable tumor microenvironments, which would result in better clinical outcomes, using the cancer genome atlas (TCGA) cohort with 371 patients with HCC. We found CYT-high HCCs were associated with higher expressions of the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3), well-known mutagenic enzymes. Further, higher numbers of anti-cancer immune cells, such as CD8+ T cells and M1 macrophages, were infiltrated in CYT-high HCCs. Major T cell exhaustion markers were expressed significantly higher in CYT-high HCCs, likely as a negative feedback loop. Additionally, CYT-high HCCs strongly enriched gene sets related with enhanced immune activity. With strong immunity, patients with CYT-high HCCs had significantly longer disease-specific survival (DSS) and overall survival (OS) ( = 0.03 and <0.01). Furthermore, when the OS is stratified by exhaustion marker expressions, the CYT-high/exhaustion-low group had the best and CYT-low/exhaustion-high groups had the worst OS. Lastly, high CYT was an independent protective factor for prognosis. In conclusion, CYT-high HCCs were associated with enhanced immunity and better survival. Our findings suggest that proper identification of tumor-immune microenvironments could stratify the patients for appropriate treatments.
由颗粒酶A和穿孔素表达定义的细胞溶解活性评分(CYT)是潜在免疫的一个有用标志物。我们假设,使用癌症基因组图谱(TCGA)队列中371例肝细胞癌(HCC)患者,CYT高的肝细胞癌具有更强的免疫原性和良好的肿瘤微环境,这将导致更好的临床结果。我们发现CYT高的HCC与载脂蛋白B mRNA编辑酶催化多肽样3(APOBEC3)的高表达相关,APOBEC3是众所周知的诱变酶。此外,CYT高的HCC中浸润了更多数量的抗癌免疫细胞,如CD8 + T细胞和M1巨噬细胞。主要的T细胞耗竭标志物在CYT高的HCC中表达明显更高,这可能是一个负反馈回路。此外,CYT高的HCC强烈富集与增强免疫活性相关的基因集。由于具有强大的免疫力,CYT高的HCC患者具有明显更长的疾病特异性生存期(DSS)和总生存期(OS)(= 0.03和<0.01)。此外,当按耗竭标志物表达对OS进行分层时,CYT高/耗竭低组的OS最好,CYT低/耗竭高组的OS最差。最后,高CYT是预后的独立保护因素。总之,CYT高的HCC与增强的免疫力和更好的生存率相关。我们的研究结果表明,正确识别肿瘤免疫微环境可以对患者进行分层以便进行适当的治疗。