Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Immunother Cancer. 2020 Apr;8(1). doi: 10.1136/jitc-2019-000394.
Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have clinical activity in hepatocellular carcinoma (HCC), but only a subset of patients respond to these therapies, highlighting a need for novel biomarkers to improve clinical benefit. HCC usually occurs in the setting of liver cirrhosis from chronic hepatitis B or C viral infection, but the effects of viral status on the tumor immune microenvironment and clinical responses to ICIs in HCC remains unclear.
We conducted a meta-analysis to estimate the objective response rates for PD-1/PD-L1 inhibitors in virally-infected and uninfected patients, and examined the effects of viral etiology on the tumor microenvironment using data from The Cancer Genome Atlas, as well as peripheral blood responses using an independent cohort of patients studied by mass cytometry (cytometry by time-of-flight (CyTOF)).
Meta-analysis comparing objective response rates (ORR) between virally-infected and uninfected patients showed no clinically meaningful difference (absolute difference of ORR in virally-infected vs uninfected=-1.4%, 95% CI: -13.5% to 10.6%). There was no relationship between viral etiology on features of the tumor immune microenvironment that are known to modulate responses to PD-1/PD-L1 inhibitors, and the tumor mutational burden was similar between virally-infected and uninfected HCC. RNA sequencing of tissue-resident T cell and B cell repertoires similarly showed no effect of viral status on their diversity. CyTOF analysis of peripheral blood specimens further demonstrated similar expression of immune-related markers in response to PD-1 inhibitor therapy in virally-infected and uninfected HCC.
There is no significant effect of viral etiology on the tumor immune microenvironment in HCC, and viral status should not be used as a criterion to select patients for PD-1/PD-L1 therapy.
针对程序性细胞死亡蛋白 1（PD-1）/程序性死亡配体 1（PD-L1）通路的免疫检查点抑制剂（ICIs）在肝细胞癌（HCC）中具有临床活性，但只有一部分患者对这些治疗有反应，这凸显了需要新的生物标志物来提高临床获益。HCC 通常发生在慢性乙型或丙型肝炎病毒感染引起的肝硬化背景下，但病毒状态对 HCC 肿瘤免疫微环境和对 ICIs 的临床反应的影响尚不清楚。
我们进行了一项荟萃分析，以估计 PD-1/PD-L1 抑制剂在病毒感染和未感染患者中的客观缓解率，并使用癌症基因组图谱的数据检查病毒病因对肿瘤微环境的影响，以及使用独立的患者群体使用飞行时间质谱流式细胞术（CyTOF）进行的外周血反应。
比较病毒感染和未感染患者客观缓解率（ORR）的荟萃分析显示，两者之间没有临床意义上的差异（病毒感染与未感染相比 ORR 的绝对差异=-1.4%，95%CI：-13.5%至 10.6%）。病毒病因与已知调节 PD-1/PD-L1 抑制剂反应的肿瘤免疫微环境特征之间没有关系，病毒感染和未感染 HCC 的肿瘤突变负担相似。组织驻留 T 细胞和 B 细胞库的 RNA 测序同样表明，病毒状态对其多样性没有影响。CyTOF 分析外周血标本进一步表明，在病毒感染和未感染的 HCC 中，对 PD-1 抑制剂治疗的免疫相关标志物的表达相似。
病毒病因对 HCC 肿瘤免疫微环境没有显著影响，病毒状态不应作为选择 PD-1/PD-L1 治疗患者的标准。
