Programmed death ligand 1 as an indicator of pre-existing adaptive immune responses in human hepatocellular carcinoma

Abstract

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.

Mechanism and prognostic value of indoleamine 2,3‐dioxygenase 1 expressed in hepatocellular carcinoma

“…CD4+ T cells and NK cells are also sources of IFN‐γ in the tumor microenvironment, but the results of IHC analyses showed no correlation between T‐IDO1 expression and CD4+ T cell or NK cell infiltration. These findings are consistent with our reported quantitative PCR results in freshly resected HCC tissues, which showed no correlation between IFNG and CD4 or CD56 at the mRNA level . This might be due to NK cells seldom infiltrating into HCC, and there is not only Th1 in CD4+ T cells in the HCC microenvironment …”

“…Patients with low levels of T‐IDO1 expression were older than patients with high levels, which could be explained by decreased production of cytokines and lower per‐cell cytotoxicity, resulting from innate immunosenescence . Thus, overexpression of the immunosuppressive molecule IDO1 by tumors positively correlates with enhanced antitumor immunity, and our seemingly contradictory conclusion has been supported by many previous studies in other tumors …”

“…39 Thus, overexpression of the immunosuppressive molecule IDO1 by tumors positively correlates with enhanced antitumor immunity, and our seemingly contradictory conclusion has been supported by many previous studies in other tumors. 21,23,34 Indoleamine 2,3-dioxygenase 1-positive cells were also detected in inflammatory infiltration in all cases, and I-IDO1 expression positively correlated with OS, although it might be not an independent predictor. Extensive mechanistic studies disclosed that I-IDO1 upregulation elicited by multiplex cytokines existed with inflammatory infiltration; in turn, high I-IDO1 expression could downregulate inflammatory factors, and tumor cell proliferation was sequentially slowed.…”

“…21,32,33 In vitro cul- HCC tissues, which showed no correlation between IFNG and CD4 or CD56 at the mRNA level. 34 This might be due to NK cells seldom infiltrating into HCC, and there is not only Th1 in CD4+ T cells in the HCC microenvironment. 35 Notably, T-IDO1 staining was not proportional to infiltrating resulting from innate immunosenescence.…”

A Four-Factor Immunoscore System That Predicts Clinical Outcome for Stage II/III Gastric Cancer

“…Consistently, our IHC results showed that PD-L1 expression in TC is mainly detected in areas surrounded by gatherings of immune cells in gastric cancer tissues, with correlations between TC PD-L1 and more infiltration of CD8 þ T cell confirmed by the Spearman test. Patients with PD-L1 þ tumor cells and CD8 More T cells have the best prognosis compared to other groups, indicating an adaptive immune status existing in gastric cancer patients, consistent with reports in melanoma and hepatocellular carcinoma (39,40), although PD-L1 has been reported to correlate with the worse survival of gastric cancer patients (14). A possible explanation for the contrary results is the different patient populations enrolled.…”