Programmed death ligand 1 as an indicator of pre-existing adaptive immune responses in human hepatocellular carcinoma.
It is well known that the aberrant expression of programmed death ligand 1 (PD-L1) on tumor cells impairs antitumor immunity. To date, in hepatocellular carcinoma (HCC), the relationship between PD-L1 expression and host-tumor immunity is not well defined. Here, the expression levels of PD-L1 and CD8(+) T cell infiltration were analyzed by immunohistochemistry (IHC) in formalin fixed paraffin embedded (FFPE) specimens from 167 HCC patients undergoing resection. A significant positive association was found between PD-L1 expression and the presence of CD8(+) T cell (p < 0.0001). Moreover, constitutive PD-L1 protein expression was not detected by western blot in HepG2, Hep3B, and 7402 HCC cancer cell lines; but co-cultured these cell lines with INFγ, a cytokine produced by activated CD8(+) T cells, remarkably upregulated PD-L1 expression. In fresh frozen HCC specimens, INFγ was found to be significantly correlated with PD-L1 and CD8(+) gene expression, as evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). These findings indicate that increased PD-L1 level may represent an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity. Both increased intratumoral PD-L1 and CD8(+) were significantly associated with superior DFS (CD8(+): p = 0.03; PD-L1: p = 0.023) and OS (CD8(+): p = 0.001 and PD-L1: p = 0.059), but PD-L1 expression was not independently prognostic. In conclusions, PD-L1 upregulation is mainly induced by activated CD8(+) cytotoxic T cells pre-existing in HCC milieu rather than be constitutively expressed by the tumor cells, and it is a favorable prognostic factor for HCC.
Minimally Invasive Interventional Division, Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, China.
Qian-Kun
QK
Xie
Minimally Invasive Interventional Division, Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Clinical Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
Yu-Jie
YJ
Zhao
Department of Interventional Radiology, The Third Affiliated Hospital, Sun Yat-sen University , Guangzhou, China.
Tao
T
Pan
Minimally Invasive Interventional Division, Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, China.
Ning
N
Lyu
Minimally Invasive Interventional Division, Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, China.
Lu-Wen
LW
Mu
Minimally Invasive Interventional Division, Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, China.
Shao-Long
SL
Li
Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, China.
Mu-De
MD
Shi
Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, China.
Zhen-Feng
ZF
Zhang
Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, China.
Peng-Hui
PH
Zhou
Minimally Invasive Interventional Division, Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center , Guangzhou, China.
Ming
M
Zhao
Adaptive immune resistance; CD8+; INFγ; innate immune resistance; prognosis